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J G Huijmans

Publications and source records attributed to J G Huijmans.

At least 19 recordsLinked to original sources
PubMed2005

Two novel mutations in SLC6A8 cause creatine transporter defect and distinctive X-linked mental retardation in two unrelated Dutch families.

Four Dutch male patients, two brothers from unrelated families were referred for investigation of psychomotor and severe language/speech delay. All four patients showed growth deficiency over the years. Facial features and poor body habitus were quite similar in the patients and in their mothers. Brain MRI showed nonspecific periventricular white matter lesions. In all the patients neuropsychological tests revealed moderate mental retardation, attention deficit and hyperactivity with impulsivity, a semantic-pragmatic language disorder, and oral dyspraxia. This specific cognitive profile is different from other children with mental retardation syndromes and seems to be unique. Excretion of creatine to creatinine ratio in urine of the four boys was increased compared to controls and their creatine uptake in fibroblasts was deficient. In the two brothers from the first pedigree, DNA sequence analysis revealed a novel mutation in the splice donor site in intron 10 (IVS10 + 5G>C, c.1495 + 5G>C) of the SLC6A8 gene leading to skipping of exon 10. In the other sib pair a novel missense mutation (c. 1361C>T; p.Pro544Leu) was found. These are the first families reported, in which the clinical suspicion of a creatine transporter disorder was raised on clinical grounds, before a brain 1H-MRS suggested the diagnosis. Screening of apparently X-linked mental retarded patients with this somatic and behavioral phenotype by the biochemical assay of creatine to creatinine ratio in the urine or DNA sequence analysis of SLC6A8 is worthwhile even when 1H-MRS is not available.

Base Sequence↗
PubMed2001

Pitfalls in the diagnosis of multiple sulfatase deficiency.

Multiple sulfatase deficiency (MSD, OMIM 272200) is an autosomal recessive leukodystrophy associated with the deficiency of several, in total seven, sulfatases. The disorder is clinically and biochemically variable. The clinical picture combines features of mucopolysaccharidosis and metachromatic leukodystrophy (MLD, OMIM 250100) in a variable spectrum. Here we report a 3-year old Iranian girl with an MLD-like presentation of MSD. Arylsulfatase A deficiency and sulfatide excretion were found. Differently from what was previously reported in the literature, this girl never showed abnormal mucopolysaccharide excretion in the urine. There were no additional visceral or skeletal signs. She was originally diagnosed as having MLD. Only when she developed ichthyosis were seven additional sulfatases measured. In leukocytes, arylsulfatase A, steroid sulfatase and N-acetylglucosamine-6 sulfatase were profoundly deficient, while iduronate-2 sulfatase and arylsulfatase B were moderately reduced. In fibroblasts, N-acetylglucosamine-6 sulfatase was deficient, while arylsulfatase A was moderately reduced. This case illustrates the possible pitfalls in the clinical and laboratory diagnosis of MSD.

Brain↗
PubMed2000

Genomic organization of the human phosphomannose isomerase (MPI) gene and mutation analysis in patients with congenital disorders of glycosylation type Ib (CDG-Ib).

CDG-Ib is the "gastro-intestinal" type of the congenital disorders of glycosylation (CDG) and a potentially treatable disorder. It has been described in patients presenting with congenital hepatic fibrosis and protein losing enteropathy. The symptoms result from hypoglycosylation of serum- and other glycoproteins. CDG-Ib is caused by a deficiency of mannose-6-phosphate isomerase (synonym: phosphomannose isomerase, EC 5.3.1.8), due to mutations in the MPI gene. We determined the genomic structure of the MPI gene in order to simplify mutation detection. The gene is composed of 8 exons and spans only 5 kb. Eight (7 novel) different mutations were found in seven patients with a confirmed phosphomannose isomerase deficiency, analyzed in the context of this study: six missense mutations, a splice mutation and one insertion. In the last, the mutation resulted in an unstable transcript, and was hardly detectable at the mRNA level. This emphasizes the importance of mutation analysis at the genomic DNA level.

Congenital Disorders of Glycosylation↗
PubMed2000

Characterization of a novel mitochondrial DNA deletion in a patient with a variant of the Pearson marrow-pancreas syndrome.

We have recently diagnosed a patient with anaemia, severe tubulopathy, and diabetes mellitus. As the clinical characteristics resembled Pearson marrow-pancreas syndrome, despite the absence of malfunctioning of the exocrine pancreas in this patient, we have performed DNA analysis to seek for deletions in mtDNA. DNA analysis showed a novel heteroplasmic deletion in mtDNA of 8034bp in length, with high proportions of deleted mtDNA in leukocytes, liver, kidney, and muscle. No deletion could be detected in mtDNA of leukocytes from her mother and young brother, indicating the sporadic occurrence of this deletion. During culture, skin fibroblasts exhibited a rapid decrease of heteroplasmy indicating a selection against the deletion in proliferating cells. We estimate that per cell division heteroplasmy levels decrease by 0.8%. By techniques of fluorescent in situ hybridisation (FISH) and mitochondria-mediated transformation of rho(o) cells we could show inter- as well as intracellular variation in the distribution of deleted mtDNA in a cell population of cultured skin fibroblasts. Furthermore, we studied the mitochondrial translation capacity in cybrid cells containing various proportions of deleted mtDNA. This result revealed a sharp threshold, around 80%, in the proportion of deleted mtDNA, above which there was strong depression of overall mitochondrial translation, and below which there was complementation of the deleted mtDNA by the wild-type DNA. Moreover, catastrophic loss of mtDNA occurred in cybrid cells containing 80% deleted mtDNA.

Amino Acid Sequence↗
PubMed2000

Type I sialidosis: a clinical, biochemical and neuroradiological study.

We report biochemical, morphological and neuroradiological findings in a 40-year-old woman affected with type I sialidosis. The clinical symptoms, consisting of a cerebellar syndrome, were first noted at the age of 17 years. The macular cherry-red spot was first observed after 23 years of disease. A CT scan performed at 21 years of age showed enlargement of the fourth ventricle. Nuclear magnetic resonance imaging of the brain performed at the age of 40 showed severe atrophy of the cerebellum and pontine region; atrophy of cerebral hemispheres and of the corpus callosum was also observed. We emphasize the prolonged course of illness in this patient, observed over a long period of time. Of particular interest is the neuroradiological study showing our findings both at the beginning of the disease and after 20 years.

Adult↗
PubMed2000

Functional hyperactivity of hepatic glutamate dehydrogenase as a cause of the hyperinsulinism/hyperammonemia syndrome: effect of treatment.

OBJECTIVE: The combination of persistent hyperammonemia and hypoketotic hypoglycemia in infancy presents a diagnostic challenge. Investigation of the possible causes and regulators of the ammonia and glucose disposal may result in a true diagnosis and predict an optimum treatment. PATIENT: Since the neonatal period, a white girl had been treated for hyperammonemia and postprandial hypoglycemia with intermittent hyperinsulinism. Her blood level of ammonia varied from 100 to 300 micromol/L and was independent of the protein intake. METHODS: Enzymes of the urea cycle as well as glutamine synthetase and glutamate dehydrogenase (GDH) were assayed in liver tissue and/or lymphocytes. RESULTS: The activity of hepatic GDH was 874 nmol/(min.mg protein) (controls: 472-938). Half-maximum inhibition by guanosine triphosphate was reached at a concentration of 3.9 micromol/L (mean control values:.32). The ratio of plasma glutamine/blood ammonia was unusually low. Oral supplements with N-carbamylglutamate resulted in a moderate decrease of the blood level of ammonia. The hyperinsulinism was successfully treated with diazoxide. CONCLUSION: A continuous conversion of glutamate to 2-oxoglutarate causes a depletion of glutamate needed for the synthesis of N-acetylglutamate, the catalyst of the urea synthesis starting with ammonia. In addition, the shortage of glutamate may lead to an insufficient formation of glutamine by glutamine synthetase. As GDH stimulates the release of insulin, the concomitant hyperinsulinism can be explained. This disorder should be considered in every patient with postprandial hypoglycemia and diet-independent hyperammonemia.

Ammonia↗
PubMed2000

First-trimester diagnosis of Morquio disease type A.

Since the introduction in 1990 of a novel fluorogenic substrate for galactose-6-sulphate sulphatase we have used this substrate for prospective prenatal diagnosis in 10 pregnancies at risk for Morquio disease type A. Chorionic villi were analysed in five cases. The results indicated an affected fetus in one pregnancy which represents the first case of first-trimester diagnosis of this disorder; heterozygosity was demonstrated in two cases. Following amniocentesis, two affected fetuses and one heterozygote were diagnosed. The results of the present prospective prenatal analyses confirm our previous retrospective studies and demonstrate the reliability and convenience of the 4-methylumbelliferyl substrate.

Amniocentesis↗
PubMed1999

Juvenile hyaline fibromatosis: clinical heterogeneity in three patients.

BACKGROUND: Systemic hyalinoses are genetic generalized fibromatoses characterized by an accumulation of hyalin in the dermis. Two distinctive syndromes are recognized in the literature: infantile systemic hyalinosis (ISH) and juvenile hyaline fibromatosis (JHF). ISH and JHF are sometimes difficult to separate since they show significant overlap. OBSERVATIONS: We report on 3 children from two unrelated families suffering from JHF. The first child is severely handicapped by joint contracture, massive hyperplasia of the gingivae, diffuse skin papules and subcutaneous nodules occupying the scalp, face, perianal area, palms, soles and chest. At the same age, the second child only shows pearly skin papules on the face, groin and perianal area and gingival hyperplasia without joint stiffness or any other subjective complaint. The third patient, a brother of the second child, developed mild skin abnormalities by the end of the first year. The occurrence in siblings and consanguinity in the second family suggests autosomal recessive inheritance. Histological skin examination in the 3 cases showed hyaline deposition in the dermis and abnormal ultrastructure of fibroblasts. Biochemical findings showed mucopolysaccharide abnormalities in both families. CONCLUSION: Our patients do not only illustrate the different expressions of JHF but also show some overlap with ISH, suggesting a common cause for both disorders. Genetic studies will finally answer this question.

Child, Preschool↗
PubMed1998

Clinical, biochemical and molecular findings in a two-generation Morquio A family.

Mucopolysaccharidosis type IVA (Morquio A) is caused by a deficiency of N-acetylgalactosamine-6-sulfatase (GALNS), an enzyme capable of cleaving the sulfate group from both N-acetylgalactosamine-6-sulfate and galactose-6-sulfate. We describe here a two-generation Morquio A family with two distinct clinical phenotypes. The two probands from the second generation showed intermediate signs of the disease whereas their affected mother, aunt and two uncles had only very mild symptoms. Galactose-6-sulfatase (GALS) activity in leukocytes and fibroblasts of the affected family members was clearly deficient. Molecular genetic analysis of the GALNS gene revealed that two different point mutations segregate in the family, which correlated well with the clinical phenotype. The probands with intermediate symptoms were compound heterozygotes for the mutations R259Q and R94G, the latter one being inherited from the unaffected father. The mother and her affected siblings with the unusually mild phenotype were proven to be homozygous for the novel missense point mutation R259Q.

Adolescent↗
PubMed1997

L-2-hydroxyglutaric aciduria: clinical heterogeneity versus biochemical homogeneity in a sibship.

Three out of four sibs in a North-African family were affected with L-2-hydroxyglutaric aciduria. The youngest sib was most severely handicapped: she was diagnosed at 2.5 years of age, whereas the then 7- and 10-year-old siblings had a less pronounced psychomotor retardation. All patients had an increased head circumference in contrast to the healthy, non-affected sibling. Urine and plasma levels of L-2-hydroxyglutaric acid in the three sibs were similar and showed only a small variation. Magnetic resonance imaging (MRI) of the brain in the eldest sib showed hyperintense signal on T2-weighted images of the basal ganglia, dentate nucleus and subcortical white matter. The youngest sib showed identical white matter abnormalities of the corpus medullare cerebelli. These abnormalities were consistent with demyelination and/or spongiosis. On two occasions cerebrospinal fluid amino acid chromatography in the youngest sib showed an increased concentration of lysine and a decreased level of glutamine. Plasma lysine was normal. It is concluded that L-2-hydroxyglutaric aciduria is almost invariably associated with neurological disease; the severity of the symptoms does not seem to be completely dependent on the extent of the biochemical abnormalities and may even be variable within a family.

Ataxia↗
PubMed1996

Identification of glycosaminoglycans in age-related macular deposits.

We investigated the presence and localization of glycosaminoglycans in basal laminar deposit and drusen in age-related maculopathy. Conventional histological staining techniques and monoclonal antibodies specific for several glycosaminoglycans were used on paraffin-embedded human maculae. Furthermore, macular homogenates were analyzed with two-dimensional electrophoresis. Quantitative analysis of glycosaminoglycans was done spectrophotometrically using dimethylmethylene blue. Immunohistochemically, all basal laminar deposit stained positive for chondroitin 4-sulfate and focally positive for heparan sulfate proteoglycan. Drusen were not stained with any of the monoclonal antibodies. With two-dimensional electrophoresis, it was demonstrated that macular extracts with and without age-related maculopathy contained chondroitin sulfate. Heparan sulfate was only expressed in maculae with age-related maculopathy. The total amount of glycosaminoglycans was significantly higher in maculae with basal laminar deposit than in maculae without basal laminar deposit (P = .001). There were significant differences in the amount and composition of glycosaminoglycans between maculae with and without age-related maculopathy.

Aged↗
PubMed1996

Prenatal diagnosis of Sanfilippo A syndrome: experience in 35 pregnancies at risk and the use of a new fluorogenic substrate for the heparin sulphamidase assay.

We have investigated the use of a 4-methylumbelliferone (MU)-derived artificial substrate, MU-alpha-D-N-sulphoglucosaminide, for the sulphamidase assay in chorionic villi and amniotic fluid cells. In the new two-step enzyme assay, fluorescent MU is released by the successive action of endogenous sulphamidase and an added yeast enzyme preparation which hydrolyses the MU-alpha-glucosaminide intermediate. Optimal conditions for a sensitive, accurate, and convenient procedure for use in the prenatal diagnosis of Sanfilippo A syndrome are described. Previously, prenatal diagnosis of Sanfilippo A syndrome has been achieved by a radioactive sulphamidase assay in chorionic villi or in cultured amniocytes and by two-dimensional electrophoresis of glycosaminoglycans in amniotic fluid. Our experience using these methods in 35 pregnancies at risk is reported. The feasibility of the new fluorogenic assay was evaluated by retrospective testing of stored homogenates of chorionic villi and amniotic fluid cells from 22 pregnancies at risk. Unequivocal assignment of the fetal status in five affected pregnancies and 17 pregnancies with a normal outcome confirms the reliability of the new sulphamidase assay, which is in every respect more convenient than the conventional method using 35S-radiolabelled heparin.

Amniocentesis↗
PubMed1996

Amniotic fluid odd-chain fatty acids are increased in propionic acidaemia.

Odd-chain (C15 and C17) fatty acids have been reported to accumulate in tissues and body fluids of patients with propionic and methylmalonic acidaemia. We investigated the occurrence of these substances in amniotic fluid samples. The odd-chain fatty acid levels (expressed as the percentage of total C12-C20 fatty acids) in eight control samples ranged from 3.7 to 12.5 per cent. Three samples from affected propionic acidaemia pregnancies had values of 15.3-22.9 per cent; one methylmalonic acidaemia sample had a normal level of 9.3 per cent. These results supply further evidence of the prenatal accumulation of odd-chain fatty acids in propionic acidaemia.

Amino Acid Metabolism, Inborn Errors↗
PubMed1996

Intracellular amino acid concentrations in children with chronic renal insufficiency.

We studied amino acid concentrations in granulocytes and plasma of 24 children with chronic renal failure and 15 healthy children. Granulocytes were isolated from 10 ml of blood using a dextran-Ficoll-Hypaque procedure. Intracellular levels of leucine, isoleucine, methionine, phenylalanine, lysine, histidine, tyrosine, and arginine were significantly lower in children with chronic renal failure than healthy children. There were no significant differences in intracellular and plasma amino acid concentrations between children with chronic renal failure on a well-balanced protein-restricted diet and children with chronic renal failure with a normal protein intake.

Adolescent↗
PubMed1996

Plasma total odd-chain fatty acids in the monitoring of disorders of propionate, methylmalonate and biotin metabolism.

Total plasma odd-numbered long-chain fatty acids were analysed in patients with methylmalonic acidaemia (vitamin B12-responsive and unresponsive), combined methylmalonic acidaemia/homocystinuria (CblC), propionic acidaemia (both neonatal-onset and late-onset), biotinidase deficiency and holocarboxylase synthase deficiency, as well as in hospital controls. Total odd-numbered long-chain fatty acids (C15:0, C17:1 and C17:0) were expressed as a percentage of total C12-C20 fatty acids. Control values were 0.72% +/- 0.31% (n = 12). Normalization of the percentage of odd-chain fatty acids occurred in all vitamin-responsive patients, following the institution of vitamin treatment. In general the neonatal-onset propionic acidaemia and B12-unresponsive methylmalonic acidaemia patients had the highest plasma odd-chain fatty acid concentrations, which correlated with the clinical condition but not with the urinary excretion of methylcitrate or methylmalonate. Plasma odd-chain fatty acid concentrations and methylmalonate excretions in CblC patients reacted very well to vitamin B12 treatment, but with no clinical response. Measurement of plasma odd-chain fatty acids is of no value for the monitoring of defects of biotin metabolism.

Adolescent↗