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At least 19 recordsLinked to original sources
PubMed1998

Impaired oral health in patients with aspartylglucosaminuria.

OBJECTIVE: The aim of this study was to assess the oral health of patients with aspartylglucosaminuria, a heritable lysosomal storage disorder, and to recommend guidelines for treatment. STUDY DESIGN: Eighty-two patients with aspartylglucosaminuria and 122 control subjects were examined clinically; in addition, panoramic radiographs were evaluated in 61 patients with aspartylglucosaminuria and 61 control subjects. RESULTS: High prevalences of caries, gingivitis, and oral Candida (P < .001), extensive gingival overgrowths (18%; P < .001), benign odontogenic tumors or tumorlike lesions (8%; P = .057), reduced maxillary sinuses (P < .001), limited mouth opening (P < .001), and food retention in the mouth (45%) were the major oral findings that distinguished the patients with aspartylglucosaminuria from the control subjects. Adults with aspartylglucosaminuria had diverse oral health problems, early loss of several permanent teeth being the most disabling feature. CONCLUSIONS: Patients with aspartylglucosaminuria appear to be at a higher risk for a number of oral disorders; however, poor oral hygiene and failure to cooperate increase these patients' risk of dental and periodontal diseases, making successful prevention crucial.

Acetylglucosamine↗
PubMed2006

Sleep disturbances in aspartylglucosaminuria (AGU): a questionnaire study.

Sleep disturbances are common in many progressive metabolic encephalopathies. The possible presence of disturbed sleep-wake behaviour in the lysosomal storage disorder aspartylglucosaminuria, has not been previously studied, however. The sleep-wake behaviour of 81 patients with aspartylglucosaminuria (AGU, age 3-55 years, median 22 years; 42 female and 39 male) and 49 controls (age 2-57 years, median 18 years; 25 female and 24 male) was assessed through a postal survey. A slightly modified version of the validated Basic Nordic Sleep Questionnaire was used. Fifty-eight per cent of the AGU patients were reported to suffer daily from a sleep-related problem (controls 31%, p < 0.01). In AGU adults (age >17 years) and children (age < or =17 years), the corresponding figures were 52% and 61%, respectively (control children 22%, p < 0.05 and control adults 38%, p = 0.06). In AGU children, settling difficulties were reported to occur significantly more commonly than in control children. Children with AGU were also reported to snore more often than were the controls. Adults with this disorder were found to suffer from severely fragmented night-time sleep, which was experienced as highly distressing by the parents and other caregivers. A long night sleep period was reported to be common in the ageing AGU patients (AGU 9.5 +/- 1.7 vs controls 7.2 +/- 1.0 h, mean +/- SD, p < 0.001). Parents and caregivers also often complained about disturbing movements during sleep in AGU patients. In conclusion, both children and adults with aspartylglucosaminuria were reported to display several types of sleep disturbances significantly more commonly than healthy controls.

Acetylglucosamine↗
PubMed1976

Isolation of the liver N-aspartyl-beta-glucosaminidase in aspartylglucosaminuria.

The isolation of liver N-aspartyl-beta-glucosaminidase in human aspartylglucosaminuria, where this enzyme activity is diminished, yields an enzyme molecule with the same molecular weight and pH optimum as the normal enzyme. Its activity is 10% of that of the control preparation. Combination of both enzymes results in the summation of both activities, and the pathological enzyme does not inhibit the control preparation. It is concluded that no change into a totally different isoenzyme has occurred in aspartylglucosaminuria.

Amidohydrolases↗
PubMed2001

Bone marrow transplantation for aspartylglucosaminuria: follow-up study of transplanted and non-transplanted patients.

We describe the state of health, intellectual skills, and dysmorphic features of 19 young patients with aspartylglucosaminuria. Of them, 5 had undergone a successful bone marrow transplantation between 1991 and 1997. The first 2 patients who received transplants were, after 7 and 5 years' follow-up, more severely mentally retarded than the non-transplanted patients. The general health of the later patients was quite good, whereas the 5 patients who underwent bone marrow transplantation had post-transplant complications. Their dysmorphic status remained unchanged. We cannot encourage bone marrow transplantation for the treatment of patients with aspartylglucosaminuria after infancy.

Aspartylglucosaminuria↗
PubMed1997

Aspartylglucosaminuria: radiologic course of the disease with histopathologic correlation.

Twelve living patients (aged 19 months to 32 years) with aspartylglucosaminuria were examined by magnetic resonance imaging (MRI), and the magnetic resonance (MR) images of 16 health volunteers (aged 4 to 32 years) were used as controls. One patient was examined twice. Postmortem MRI and histopathologic analysis were done on the brains of four additional adult patients. Signal intensities determined quantitatively on T2-weighted images differed significantly between patients and controls, being higher from the white matter (P < .0002) and lower from the thalami (P < .03) in the patients. The generally increased signal intensity of the white matter was most obvious in the young patients, with many focal areas of very high signal intensity in the subcortical white matter. The subcortical white matter showed a somewhat increased signal intensity even at the age of 32 years. In two of the four postmortem MR images, the distinction between the gray and white matter was still poor. At histopathologic analysis, the basic cortical cytoarchitecture was generally preserved but most neurons contained vacuoles, which were also found in the neurons of the deep gray matter. In two of the four autopsy cases the white matter showed diffuse pallor of myelin staining and some gliosis. Thus aspartylglucosaminuria is primarily a gray-matter disease also affecting white matter by delaying myelination.

Acetylglucosamine↗
PubMed1976

Enzymatic diagnosis and carrier detection of aspartylglucosaminuria using blood samples.

The activity of the glycoprotein degrading lysosomal hydrolase, 4-L-aspartylglycosylamine amido hydrolase (AAD Gase, EC.3.5.1.26), was measured in plasma, buffy coat leukocytes, and separated lymphocytes (Ficoll separation) from 16 patients with aspartylglucosaminuria (AGU), 29 obligate heterozygotes, and 30 control subjects. In lymphocytes the AGU patients had unmeasurable or minimal AAD Gase activity with a mean of 3.9 U. The obligate heterozygotes showed AAD Gase activities ranging from 5 to 69 U with a mean of 34.1 U. Enzyme activities in the control group ranged from 91 to 243 U with a mean of 127.9 U, and were clearly separated from the values of the heterozygotes. In leukocytes the AGU patients had unmeasurable enzyme activity and obligate heterozygotes had enzyme levels closely similar to those in the lymphocytes from the same individuals. The AAD Gase activity in the leukocytes of the control group displayed a much wider variation than in the lymphocytes, ranging from 22 to 132 U with a mean of 70.7 U. In plasma the AGU patients had undetectable AAD Gase activity. The mean enzyme level of obligate heterozygotes was 72.2 U and that of control individuals 107.2 U, but the overlap between the groups was extensive. The results indicate that homozygous deficiency of AAD Gase, i.e., aspartylglucosaminuria can be reliably diagnosed using plasma, leukocytes, or separated lymphocytes. For carrier detection only separated lymphocytes allow a satisfactory differentiation between heterozygous and normal individuals. A group of 31 siblings of verified AGU cases and 11 children of identified carriers, whose spouses had normal AAD Gase activity, were investigated using the lymphocyte assay. The observed and expected frequencies (on the basis of Mendelian probabilities) were closely similar, suggesting that the lymphocyte assay can be used reliably for carrier detection.

Acetylglucosaminidase↗
PubMed1998

Aspartylglucosaminuria in a Canadian family.

Aspartylglucosaminuria (McKusick 208400) is a lysosomopathy associated with aspartylglucosaminidase (L-aspartamido-beta-N-acetylglucosamine amidohydrolase, EC 3.5.1.26) deficiency. It has been most frequently encountered in Finland, where the regional incidence may be as high as 1 in 3600 births. In North America it is very rare, having been reported in only 8 patients. We encountered 4 patients with aspartylglucosaminuria in a Canadian family of 12 siblings. The 4 siblings affected--2 brothers and 2 sisters--were apparently normal at birth; however, their developmental milestones, particularly speech, were slow, and they acquired only a simple vocabulary. Throughout life, there was a progressive coarsening of facial features; 3 had inguinal hernia and recurrent diarrhea; all became severely retarded and by the 4th decade showed evident deterioration of both cognitive and motor skills; 2 exhibited cyclical behavioural changes. Three of the siblings have died, at 33, 39 and 44 years of age. Two died of bronchopneumonia and 1 of asphyxiation following aspiration. In the urine of all 4 siblings, and in the 1 liver examined, we found 2-acetamido-1-N-(4-L-aspartyl)-2-deoxy-beta-D-glucosamine (GlcNAc-Asn) and alpha-D-mannose-(1,6)-beta-D-mannose-(1,4)-2-acetamido- 2-deoxy-beta-D-glucose-(1,4)-2-acetamido-1-N-(4-L-aspartyl)-2-deoxy-beta - D-glucosamine (Man2-GlcNAc2-Asn). Compared with the level of activity in controls, aspartylglucosaminidase activity was less than 2% in fibroblasts from 3 of the siblings, less than 0.5% in leukocytes from 1 sibling, and less than 1% in the liver of 1 sibling, whereas other acid hydrolase activities in these tissues were normal. Ultrastructural studies of skin showed that fibroblasts, endothelial cells and pericytes contained vacuoles with fine reticulo-floccular material. Glial and neuronal cells of the central nervous system showed similar inclusions as well as others composed of concentric or parallel membranous arrays intermingled with lipid droplets.

Acetylglucosamine↗
PubMed1999

Toward understanding the neuronal pathogenesis of aspartylglucosaminuria: expression of aspartylglucosaminidase in brain during development.

The deficiency of a lysosomal enzyme, aspartylglucosaminidase, results in a lysosomal storage disorder, aspartylglucosaminuria, manifesting as progressive mental retardation. To understand tissue pathogenesis and disease progression we analyzed the developmental expression of the enzyme, especially in brain, which is the major source of the pathological symptoms. Highest mRNA levels in brain were detected during embryogenesis, the levels decreased neonatally and started to increase again from Day 7 on. In Western analyses, a defective processing of aspartylglucosaminidase was observed in brain as compared to other tissues, resulting in very low levels of the mature, active form of the enzyme. Interestingly immunohistochemical analyses of mouse brain revealed that aspartylglucosaminidase immunoreactivity closely mimicked the myelin basic protein immunostaining pattern. The only evident neuronal staining was observed in the developing Purkinje cells of the cerebellum from Days 3 to 10, reflecting well the mRNA expression. In human infant brain, the immunostaining was also present in myelinated fibers as well as in the Purkinje cells and, additionally, in the soma and extensions of other neurons. In the adult human brain neurons and oligodendrocytes displayed immunoreactivity whereas myelinated fibers were not stained. Our results of aspartylglucosaminidase immunostaining in myelinated fibers of infant brain might imply the involvement of aspartylglucosaminidase in the early myelination process. This is consistent with previous magnetic resonance imaging findings in the brains of aspartylglucosaminuria patients, revealing delayed myelination in childhood.

Adult↗
PubMed1993

Applications of a new fluorimetric enzyme assay for the diagnosis of aspartylglucosaminuria.

L-Aspartic acid-beta-7-amido-4-methylcoumarin is a sensitive and specific fluorogenic substrate for lysosomal glycoasparaginase (aspartylglucosaminidase). Fibroblasts and leukocytes from 8 patients with aspartylglucosaminuria, showed 1-7% of the mean normal glycoasparaginase activity. Heterozygotes showed intermediate activities. Glycoasparaginase activity in chorionic villi, cultured trophoblasts, cultured amniotic fluid cells and amniotic fluid was readily detectable, indicating that prenatal analysis of aspartylglucosaminuria should be possible with this assay. beta-Aspartyl-4-methylumbelliferone was synthesized but this potential substrate can not be used to assay glycoasparaginase since it hydrolyses spontaneously.

Acetylglucosamine↗
PubMed2004

Five-year follow-up of two siblings with aspartylglucosaminuria undergoing allogeneic stem-cell transplantation from unrelated donors.

BACKGROUND: Aspartylglucosaminuria is a rare, inherited lysosomal disease characterized by a slowly progressive mental retardation and coarse facial and body features. With the intent to provide the deficient enzyme aspartylglucosaminidase, allogeneic stem-cell transplantation (ASCT) has been attempted. Only a few cases of transplants have been reported. METHODS: Two siblings with aspartylglucosaminuria underwent allogeneic bone marrow transplants using unrelated human leukocyte antigen-A, -B, and DR identical donors at ages 10 years 5 months and 5 years 10 months, respectively. They were followed during 5 years with biochemical, neuroradiologic, neuropsychologic, and clinical investigations. RESULTS: During 5 years follow-up, no neuropsychologic or clinical deterioration was noted in the children. A stable expression of aspartylglucosaminidase was found during the whole follow-up period. The spinal fluid concentration of Tau-protein, a marker of neuronal and axonal degeneration and damage, peaked at approximately 12 months after bone-marrow transplantation and then declined to almost normal levels after 5 years. By magnetic resonance imaging (MRI), an improvement of myelination in the youngest sibling and an arrest of demyelination in the older one were observed. CONCLUSION: The importance of long-term follow-up of children after ASCT in this rare, very slowly progressive lysosomal disease must be emphasized. We report that none of the children had lost any capabilities since the transplantation; moreover, an improvement is shown in biochemical markers and MRI white-matter signals, suggesting a beneficial effect.

Acetylglucosamine↗
PubMed2023

A new horizon in the phosphorylated sites of AGA: the structural impact of C163S mutation in aspartylglucosaminuria through molecular dynamics simulation.

Aspartylglucosaminuria (AGU) is a lysosomal storage disorder caused by insufficient aspartylglucosaminidase (AGA) activity leading to chronic neurodegeneration. We utilized the PhosphoSitePlus tool to identify the AGA protein's phosphorylation sites. The phosphorylation was induced on the specific residue of the three-dimensional AGA protein, and the structural changes upon phosphorylation were studied via molecular dynamics simulation. Furthermore, the structural behaviour of C163S mutation and C163S mutation with adjacent phosphorylation was investigated. We have examined the structural impact of phosphorylated forms and C163S mutation in AGA. Molecular dynamics simulations (200&#x2009;ns) exposed patterns of deviation, fluctuation, and change in compactness of Y178 phosphorylated AGA protein (Y178-p), T215 phosphorylated AGA protein (T215-p), T324 phosphorylated AGA protein (T324-p), C163S mutant AGA protein (C163S), and C163S mutation with Y178 phosphorylated AGA protein (C163S-Y178-p). Y178-p, T215-p, and C163S mutation demonstrated an increase in intramolecular hydrogen bonds, leading to greater compactness of the AGA forms. Principle component analysis (PCA) and Gibbs free energy of the phosphorylated/C163S mutation structures exhibit transition in motion/orientation than Wild type (WT). T215-p may be more dominant among these than the other studied phosphorylated forms. It might contribute to hydrolyzing L-asparagine functioning as an asparaginase, thereby regulating neurotransmitter activity. This study revealed structural insights into the phosphorylation of Y178, T215, and T324 in AGA protein. Additionally, it exposed the structural changes of the C163S mutation and C163S-Y178-p of AGA protein. This research will shed light on a better understanding of AGA's phosphorylated mechanism.Communicated by Ramaswamy H. Sarma.

Molecular Dynamics Simulation↗
PubMed1984

Prenatal diagnosis and fetal pathology of aspartylglucosaminuria.

The prenatal diagnosis of aspartylglucosaminuria (AGU), a lysosomal storage disorder of glycoprotein degradation, was made by demonstrating the deficiency of N-aspartylglucosaminidase on cultured cells from a midterm amniotic fluid sample. Four other amniotic fluid studies from at-risk pregnancies gave a normal or a heterozygote level of enzyme activity. These pregnancies have gone to term and the delivery of healthy babies. The pregnancy with the affected fetus was terminated and the prenatal diagnosis was verified by enzyme assays on cord blood lymphocytes, cultured cells from skin biopsy, and from placental villi. Electron microscopic evidence of lysosomal storage was seen in several organs of the fetus with the notable exception of the central nervous system. The undifferentiated mesenchymal fibroblasts particularly were heavily loaded with cytoplasmic inclusions in skin, liver, kidney, and placenta.

Acetylglucosamine↗
PubMed1992

Mutations causing aspartylglucosaminuria (AGU): a lysosomal accumulation disease.

This article provides a review of the mutations reported so far in the lysosomal storage disease aspartylglucosaminuria (AGU). The clinical symptoms, biochemical findings, and diagnostic possibilities of the disease are introduced. The prevalence and biological consequences of the found mutations are then described, as well as the availability of a new rapid DNA test suitable for carrier screening. This test will be especially applicable in the genetically isolated Finnish population, where the carrier frequency of AGU was found to be as high as 1:36. Finally, future prospects dealing with the foreseeable therapeutic interventions of the disease are discussed.

Acetylglucosamine↗
PubMed1995

Identification of a novel mutation causing aspartylglucosaminuria reveals a mutation hotspot region in the aspartylglucosaminidase gene.

Aspartylglucosaminuria (AGU) is a recessively inherited metabolic disorder caused by the deficiency of a lysosomal enzyme, aspartylglucosaminidase. The worldwide most common mutation causing the disease is the AGUFin, enriched in Finland; all the other known AGU mutations are family-specific. We developed exon-specific primers to facilitate mutation search directly from the genomic DNA and identified a novel mutation, designated AGUFin minor, in seven Finnish AGUFin compound heterozygote patients. This deletion/frameshift mutation creates a premature translational termination codon and was shown to result in severely reduced transcript levels as quantified by the solid-phase minisequenching method. Genealogical data on this novel mutation suggest its relatively recent introduction into the population. The AGU mutations identified so far have been reported to be evenly distributed throughout the 1 kb coding region of the AGA cDNA. We identified a mutation hotspot region of 40 bp within the 12.5 kb AGA gene containing two previously identified mutations and the novel AGUFin minor mutation characterized in this study.

Acetylglucosamine↗
PubMed2004

A novel aspartylglucosaminuria mutation affects translocation of aspartylglucosaminidase.

The AGA gene is mutated in patients with aspartylglucosaminuria (AGU), a lysosomal storage disease enriched in the Finnish population. The disease mechanism of AGU and the biochemistry and cell biology of the lysosomal aspartylglucosaminidase (AGA) enzyme are well characterized. Here, we have investigated a novel AGU mutation found in a Finnish patient. The mutation was detected as a compound heterozygote with the Finnish major mutation in the other allele. The novel point mutation, c.44T>G, causes the L15R amino acid substitution in the signal sequence of the AGA enzyme. The mutated AGA enzyme was here analyzed by over expression in BHK and COS-1 cells. The L15R AGA protein was only faintly detectable by immunofluorescence analysis and observed in the endoplasmic reticulum. Metabolic labeling and immunoprecipitation revealed only a small amount of AGA polypeptides but the specific activity of the mutant enzyme was surprisingly high, 37% of the wild type. The amino acid substitution probably affects translocation of AGA polypeptides by altering a critical hydrophobic core structure of the signal sequence. It appears that the small amounts of active enzyme are not able to reach the lysosomes thus explaining the development of AGU disease in the patient.

Amino Acid Sequence↗
PubMed1991

Aspartylglucosaminuria: cDNA encoding human aspartylglucosaminidase and the missense mutation causing the disease.

We have isolated a 2.1 kb cDNA which encodes human aspartylglucosaminidase (AGA, E.C. 3.5.1.26). The activity of this lysosomal enzyme is deficient in aspartylglucosaminuria (AGU), a recessively inherited lysosomal accumulation disease resulting in severe mental retardation. The polypeptide chain deduced from the AGA cDNA consists of 346 amino acids, has two potential N-glycosylation sites and 11 cysteine residues. Transient expression of this cDNA in COS-1 cells resulted in increased expression of immunoprecipitable AGA protein. Direct sequencing of amplified AGA cDNA from an AGU patient revealed a G----C transition resulting in the substitution of cysteine 163 with serine. This mutation was subsequently found in all the 20 analyzed Finnish AGU patients, in the heterozygous form in all 53 carriers and in none of 67 control individuals, suggesting that it represents the major AGU causing mutation enriched in this isolated population. Since the mutation produces a change in the predicted flexibility of the AGA polypeptide chain and removes an intramolecular S-S bridge, it most probably explains the deficient enzyme activity found in cells and tissues of AGU patients.

Amino Acid Sequence↗
PubMed1989

First-trimester prenatal diagnosis of aspartylglucosaminuria.

Fetal aspartylglucosaminuria (AGU) was studied during the first trimester of pregnancy in six at-risk pregnancies using chorionic villus samples. The activity of aspartylglucosaminidase (AGA) was high in five cases, indicating an unaffected fetus. This was confirmed through delivery of healthy newborns with a normal pattern of urinary oligosaccharides. Low enzyme activity in an uncultured biopsy specimen and in cultured amniotic fluid cells in one case demonstrated that the fetus was affected. The pregnancy was terminated and the prenatal diagnosis was confirmed by showing reduced AGA activity in cultured fibroblasts of the fetus.

Amidohydrolases↗
PubMed1990

Linkage of aspartylglucosaminuria (AGU) to marker loci on the long arm of chromosome 4.

Aspartylglucosaminuria (AGU) is caused by deficient activity of the enzyme aspartylglucosaminidase (AGA). The structural gene for AGA has been assigned to the region 4q21-qter of chromosome 4. We have studied the map position of the AGU locus in relation to other marker loci on the long arm of chromosome 4 using linkage analyses. Restriction fragment length polymorphism alleles for the ADH2, ADH3, EGF, FG alpha and FG beta loci and blood group antigens for the MNS locus were determined in a panel of 12 Finnish AGU families. The heterozygous family members were identified by reduced activity of AGA in lymphocytes. Linkage studies were performed using both pairwise and multipoint analyses. Loose linkage of the AGU locus to the FG and MNS loci was observed (z = 1.16, z = 1.39, respectively). Multipoint analysis to the fixed map [ADH-(0.03)-EGF-(0.35)-FG-(0.11)-MNS] suggests that the location of the AGU locus is 0.05-0.30 recombination units distal to MNS (z = 3.03). The order cen-ADH-EGF-FG-MNS-AGU is 35 times more likely than the next best order cen-ADH-EGF-AGU-FG-MNS.

Alcohol Dehydrogenase↗