Prenatal diagnosis and fetal pathology of aspartylglucosaminuria

Aula, Pertti; Rapola, Juhani; Koskull, Harriet von; Ämmälä, Pirkko

doi:10.1002/ajmg.1320190218

Cited by 19 publications

(8 citation statements)

References 24 publications

(9 reference statements)

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“…Demonstration of accumulated aspartylglucosamine [48, 49] and other glycoasparagines in urine must lead to the measurement of glycosylasparaginase activity e.g., in serum, leukocytes or fibroblasts [50, 51]. The enzyme assay in cultured amniotic fluid cells or chorionic villus samples [52, 53] or directly in amniotic fluid enable prenatal detection of the disease. The analysis of amniotic fluid glycoasparagines may not permit reliable diagnosis of AGU [54].…”

Section: Diagnosis and Diagnostic Methodsmentioning

confidence: 99%

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Aspartylglycosaminuria: a review

Arvio

Mononen

2016

Orphanet J Rare Dis

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Aspartylglucosaminuria (AGU), a recessively inherited lysosomal storage disease, is the most common disorder of glycoprotein degradation with a high prevalence in the Finnish population. It is a lifelong condition affecting on the patient’s appearance, cognition, adaptive skills, physical growth, personality, body structure, and health. An infantile growth spurt and development of macrocephalia associated to hernias and respiratory infections are the key signs to an early identification of AGU. Progressive intellectual and physical disability is the main symptom leading to death usually before the age of 50 years.The disease is caused by the deficient activity of the lysosomal enzyme glycosylasparaginase (aspartylglucosaminidase, AGA), which leads to a disorder in the degradation of glycoasparagines – aspartylglucosamine or other glycoconjugates with an aspartylglucosamine moiety at their reducing end – and accumulation of these undegraded glycoasparagines in tissues and body fluids. A single nucleotide change in the AGA gene resulting in a cysteine to serine substitution (C163S) in the AGA enzyme protein causes the deficiency of the glycosylasparaginase activity in the Finnish population. Homozygosity for the single nucleotide change causing the C163S mutation is responsible for 98% of the AGU cases in Finland simplifying the carrier detection and prenatal diagnosis of the disorder in the Finnish population. A mouse strain, which completely lacks the Aga activity has been generated through targeted disruption of the Aga gene in embryonic stem cells. These Aga-deficient mice share most of the clinical, histopathologic and biochemical characteristics of human AGU disease. Treatment of AGU mice with recombinant AGA resulted in rapid correction of the pathophysiologic characteristics of AGU in non-neuronal tissues of the animals. The accumulation of aspartylglucosamine was reduced by up to 40% in the brain tissue of the animals depending on the age of the animals and the therapeutic protocol. Enzyme replacement trials on human AGU patients have not been reported so far. Allogenic stem cell transplantation has not proved effective in curing AGU.

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Section: Diagnosis and Diagnostic Methodsmentioning

confidence: 99%

“…AGU has been diagnosed prenatally demonstrating the deficiency of glycosylasparginase activity in cultured amniotic fluid cells [52, 53]. Electron microscopic evidence of lysosomal storage was observed in several organs including kidneys of the fetus affected by AGU.…”

Section: Fetus and Newbornmentioning

confidence: 99%

Aspartylglycosaminuria: a review

Arvio

Mononen

2016

Orphanet J Rare Dis

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“…Enzyme assays of aspartylglycosylaminase using leukocytes or cultured fibroblasts have also been employed to confirm the diagnosis. One case of aspartylglycosaminuria has been diagnosed prenatally (Aula et al, 1984) by demonstrating a deficiency of the enzyme in cultured amniotic fluid cells. MS received 27.8.87 Accepted 25.11.87 Chemical analysis of amniotic fluid glycosaminoglycans for the prenatal diagnosis of the mucopolysaccharidoses (Mossman et al, 1982) and galactosyl-oligosaccharides for GM1 gangliosidosis (Warner et al, 1983) have been described.…”

Section: Discussionmentioning

confidence: 99%

“…One amniotic fluid sample (kindly provided by Dr P. Aula, Institute of Medical Genetics, University of Turku, Finland) was from a pregnancy at t7 weeks with the fetus affected by aspartylglycosaminuria. This diagnosis was made prenatally using cultured amniotic fluid cells and confirmed by fetal pathology after abortion as previously reported (Aula et al, 1984). Eleven midterm amniotic fluid samples (15-18weeks gestation) taken from pregnancies that had gone to term with the delivery of healthy babies were used as normal controls.…”

Section: Amniotic Fluid Samplesmentioning

confidence: 92%

Amniotic fluid glycoasparagines in fetal aspartylglycosaminuria

Mononen¹,

Kaartinen²,

Mononen³

1987

J of Inher Metab Disea

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Midterm amniotic fluid samples from one pregnancy with the fetus affected by aspartylglycosaminuria and from 11 normal pregnancies were analysed for glycoasparagines accumulating in urine in aspartylglycosaminuria. The aspartylglucosamine concentration in the affected pregnancy was about five times higher than in the controls, but the absolute value was very low being only about one-thousandth of that in urine in aspartylglycosaminuria and one-tenth of that in urine samples from normal adults. In total monosaccharide analysis, only galactose content in the affected amniotic fluid was slightly elevated compared to controls, indicating that higher glycoasparagines typical of urine in aspartylglycosaminuria were not accumulated in significant amounts. The data demonstrate that the analysis of glycoasparagines in amniotic fluid is not likely to permit reliable prenatal diagnosis of aspartylglycosaminuria.

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“…A sensitive fluorometnc enzyme assay for this purpose has recently been described (19). In diagnosing fetal AGU, glycosylasparaginase activity is lacking in amniotic fluid (17) as well as in cultured amniotic fluid (20) or placental cells. However, the concentration of aspartylglucosamine in amniotic fluid is only slightly elevated (21).…”

mentioning

confidence: 99%

Aspartylglycosaminuria: protein chemistry and molecular biology of the most common lysosomal storage disorder of glycoprotein degradation

et al. 1993

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Aspartylglycosaminuria (AGU) (McKusick 20840) is the most common disorder of glycoprotein degradation caused by the failure of lysosomes to digest the protein-to-carbohydrate linkage of Asn-linked glycoproteins. During the past few years there has been significant progress in our understanding of both the protein chemistry and molecular biology of glycosylasparaginase (EC 3.5.1.26) as well as the molecular changes underlying the storage disease AGU that results from deficiency of this lysosomal hydrolase. Modern clinical assays have been developed for the diagnosis and carrier detection of this disease. Detailed structure, substrate specificity, mechanism of action, and a part of the active site of glycosylasparaginase have been defined. Molecular biology of glycosylasparaginase has progressed rapidly and already some mutations in the glycosylasparaginase gene resulting in AGU have been identified. Evolutionary aspects based on sequence data indicate a mechanistic relationship between mammalian glycosylasparaginases and bacterial/plant asparaginases.

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Prenatal diagnosis and fetal pathology of aspartylglucosaminuria

Cited by 19 publications

References 24 publications

Aspartylglycosaminuria: a review

Aspartylglycosaminuria: a review

Amniotic fluid glycoasparagines in fetal aspartylglycosaminuria

Aspartylglycosaminuria: protein chemistry and molecular biology of the most common lysosomal storage disorder of glycoprotein degradation

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