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Neurology. Genetics Jun 2024The causes of intellectual disability (ID) are varied, with as many as 1,400 causative genes. We attempted to identify the causative gene in a patient with long-standing...
OBJECTIVES
The causes of intellectual disability (ID) are varied, with as many as 1,400 causative genes. We attempted to identify the causative gene in a patient with long-standing undiagnosed ID.
METHODS
Although this was an isolated case with no family history, we searched for the causative gene using trio-based whole-exome sequencing (trio-WES), because severe ID is often caused by genetic variations, and inherited metabolic disorders (IMDs) are assumed to be the cause when regression and epilepsy occur.
RESULTS
We identified homozygous donor splice-site variants in the gene (aspartylglucosaminidase; NM_000027.4) Chr4(GRCh38):g. 177436275C>A, c.698+1G>T. This gene is implicated in aspartylglucosaminuria (AGU; OMIM #208400) and originated from both of the patient's parents. We confirmed the pathogenicity of the variant by detecting the splicing defect in cDNA from the patient's blood and accumulation of aberrant metabolites in the patient's urine.
DISCUSSION
We discuss how to more readily achieve an accurate diagnosis for patients with undiagnosed intellectual disabilities. Medical practitioners' awareness of the characteristics of the disease leading to clinical suspicion in patients with matching presentations, and the performance of newborn screening when possible, is important for the diagnosis of ID. In addition, the characteristic symptoms and course of the disease give rise to suspicion of IMDs. Given our results, we consider trio-WES to be a powerful method for identifying the causative genes in cases of ID with genetic causes.
PubMed: 38831911
DOI: 10.1212/NXG.0000000000200161 -
The Journal of Biological Chemistry Jun 1991The mutation that causes a deficiency of the lysosomal amidase, glycosylasparaginase, has been characterized in fibroblasts from three Finnish patients diagnosed with...
Characterization of the mutation responsible for aspartylglucosaminuria in three Finnish patients. Amino acid substitution Cys163----Ser abolishes the activity of lysosomal glycosylasparaginase and its conversion into subunits.
The mutation that causes a deficiency of the lysosomal amidase, glycosylasparaginase, has been characterized in fibroblasts from three Finnish patients diagnosed with aspartylglucosaminuria (AGU). The polymerase chain reaction was used to amplify the glycosylasparaginase protein coding sequence from the three AGU patients in order to compare them to the normal sequence from a full-length human placenta cDNA clone HPAsn.6 (Fisher, K.J., Tollersrud, O.K., and Aronson, N.N., Jr. (1990) FEBS Lett. 269, 440-444). Two base changes were found to be common to all three Finnish AGU patients, a G482----A transition that results in an Arg161----Gln substitution and a G488----C transversion that causes Cys163----Ser. Detection of both point mutations from PCR-amplified cDNA or genomic DNA was facilitated by their creation of new endonuclease restriction sites. Expression studies in COS-1 cells revealed only the Cys163----Ser mutation caused a deficiency of glycosylasparaginase activity. This same substitution also prevented the normal posttranslational processing of the precursor glycosylasparaginase polypeptide into its alpha and beta subunits. Cell-free expression of the single-chain glycosylasparaginase precusor did not produce an active enzyme, suggesting that post-translational generation of subunits may be required for catalytic activity.
Topics: Acetylglucosamine; Amino Acid Sequence; Aspartylglucosylaminase; Base Sequence; Blotting, Northern; Blotting, Southern; Cysteine; DNA; Fibroblasts; Finland; Humans; Lysosomes; Molecular Sequence Data; Mutation; Polymerase Chain Reaction; Protein Biosynthesis; RNA, Messenger; Restriction Mapping; Serine
PubMed: 1904874
DOI: No ID Found -
The Neuroradiology Journal Oct 2016Aspartylglucosaminuria is a rare lysosomal storage disorder that occurs as a result of a deficiency of the aspartylglucosaminidase enzyme. Because the disease is...
Aspartylglucosaminuria is a rare lysosomal storage disorder that occurs as a result of a deficiency of the aspartylglucosaminidase enzyme. Because the disease is commonly referred to as the Finnish disease heritage, it is underdiagnosed outside of Finland. To date, only three Turkish patients are described in the literature. Here we describe the clinical and brain magnetic resonance imaging findings in two Turkish cousins with aspartylglucosaminuria, which can raise the suspicion of this rare disease in clinical practice.
Topics: Aspartylglucosaminuria; Brain; Child; Child, Preschool; Family Health; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Turkey
PubMed: 27549151
DOI: 10.1177/1971400916665371 -
International Journal of Molecular... Mar 2023Novel treatment strategies are emerging for rare, genetic diseases, resulting in clinical trials that require adequate biomarkers for the assessment of the treatment...
Novel treatment strategies are emerging for rare, genetic diseases, resulting in clinical trials that require adequate biomarkers for the assessment of the treatment effect. For enzyme defects, biomarkers that can be assessed from patient serum, such as enzyme activity, are highly useful, but the activity assays need to be properly validated to ensure a precise, quantitative measurement. Aspartylglucosaminuria (AGU) is a lysosomal storage disorder caused by the deficiency of the lysosomal hydrolase aspartylglucosaminidase (AGA). We have here established and validated a fluorometric AGA activity assay for human serum samples from healthy donors and AGU patients. We show that the validated AGA activity assay is suitable for the assessment of AGA activity in the serum of healthy donors and AGU patients, and it can be used for diagnostics of AGU and, potentially, for following a treatment effect.
Topics: Humans; Aspartylglucosylaminase; Aspartylglucosaminuria; Lysosomal Storage Diseases; Lysosomes
PubMed: 36982794
DOI: 10.3390/ijms24065722 -
JIMD Reports 2017Keratan sulfate (KS) is commonly elevated in urine samples from patients with mucopolysaccharidosis type IVA (MPS IVA) and is considered pathognomonic for the condition....
Measurement of Elevated Concentrations of Urine Keratan Sulfate by UPLC-MSMS in Lysosomal Storage Disorders (LSDs): Comparison of Urine Keratan Sulfate Levels in MPS IVA Versus Other LSDs.
Keratan sulfate (KS) is commonly elevated in urine samples from patients with mucopolysaccharidosis type IVA (MPS IVA) and is considered pathognomonic for the condition. Recently, a new method has been described by Martell et al. to detect and measure urinary KS utilizing LC-MS/MS. As a part of the validation of this method in our laboratory, we studied the sensitivity and specificity of elevated urine KS levels using 25 samples from 15 MPS IVA patients, and 138 samples from 102 patients with other lysosomal storage disorders, including MPS I (n = 9), MPS II (n = 13), MPS III (n = 23), MPS VI (n = 7), beta-galactosidase deficiency (n = 7), mucolipidosis (ML) type II, II/III and III (n = 51), alpha-mannosidosis (n = 11), fucosidosis (n = 4), sialidosis (n = 5), Pompe disease (n = 3), aspartylglucosaminuria (n = 4), and galactosialidosis (n = 1). As expected, urine KS values were significantly higher (fivefold average increase) than age-matched controls in all MPS IVA patients. Urine KS levels were also significantly elevated (threefold to fourfold increase) in patients with GM-1 gangliosidosis, MPS IVB, ML II and ML II/III, and fucosidosis. Urine KS was also elevated to a smaller degree (1.1-fold to 1.7-fold average increase) in patients with MPS I, MPS II, and ML III. These findings suggest that while the UPLC-MS/MS urine KS method is 100% sensitive for the detection of patients with MPS IVA, elevated urine KS is not specific for this condition. Therefore, caution is advised when interpreting urinary keratan sulfate results.
PubMed: 27469132
DOI: 10.1007/8904_2016_1 -
Hereditas 1999Aspartylglucosaminuria (AGU) is an autosomal recessive lysosomal storage disease highly enriched in Finland where one mutation AGUFin major is responsible for 98% of the...
Aspartylglucosaminuria (AGU) is an autosomal recessive lysosomal storage disease highly enriched in Finland where one mutation AGUFin major is responsible for 98% of the AGUFin alleles. Another mutation AGUFin minor has been identified in eight compound heterozygote patients who have AGUFin major mutation in their other allele. In addition four compound heterozygote patients have AGUFin major in one allele and unknown AGUFin mutation in the other allele. To study the origin of these mutations the haplotype analysis was performed on six patients with AGUFin minor mutation and four patients with unknown AGUFin mutation using nine microsatellite markers on the 7.6 cM chromosome region on 4q28-4qter. The haplotype data suggest that one founder mutation is responsible of all AGUFin minor alleles. Allelic association was also observed in AGUFin major chromosomes. Patients with unknown mutation did not share a common haplotype and therefore most likely have different origin.
Topics: Acetylglucosamine; Alleles; Aspartylglucosaminuria; Aspartylglucosylaminase; Female; Finland; Haplotypes; Humans; Lysosomal Storage Diseases; Male; Mutation; Pedigree
PubMed: 10783529
DOI: 10.1111/j.1601-5223.1999.t01-1-00191.x -
Annals of the Rheumatic Diseases Feb 2002To ascertain whether being a carrier of an autosomal recessive disease, aspartylglucosaminuria (AGU), predisposes to chronic arthritis, as does AGU disease.
OBJECTIVE
To ascertain whether being a carrier of an autosomal recessive disease, aspartylglucosaminuria (AGU), predisposes to chronic arthritis, as does AGU disease.
METHODS
A group of 173 unrelated patients with rheumatoid arthritis (RA) but with no family members with AGU each gave a blood sample for AGUFin major mutation DNA analysis. A group of 131 AGU carriers who were parents of patients with AGU completed a questionnaire on joint symptoms and gave a blood sample for rheumatoid factor (RF) analysis. Eight RF positive parents with prolonged joint symptoms had a rheumatological evaluation.
RESULTS
Six patients (1/28) with RA were carriers of the AGUFin major mutation, whereas the carrier frequency among Finns in general is 1/50 to 1/85. Three AGU carriers had chronic arthritis (2.3%), and 17 (13%) were RF positive; the respective percentages among Finns in general are 1.4% and 5%.
CONCLUSION
As for AGU disease, carrier status may also predispose to chronic arthritis.
Topics: Adult; Aged; Arthritis, Rheumatoid; Aspartylglucosylaminase; Chronic Disease; Female; Genes, Recessive; Genetic Predisposition to Disease; Heterozygote; Humans; Male; Metabolism, Inborn Errors; Middle Aged; Mutation; Rheumatoid Factor
PubMed: 11796409
DOI: 10.1136/ard.61.2.180 -
PloS One 2017Aspartylglucosaminidase (AGA) is a low-abundance intracellular enzyme that plays a key role in the last stage of glycoproteins degradation, and whose deficiency leads to... (Comparative Study)
Comparative Study
Aspartylglucosaminidase (AGA) is a low-abundance intracellular enzyme that plays a key role in the last stage of glycoproteins degradation, and whose deficiency leads to human aspartylglucosaminuria, a lysosomal storage disease. Surprisingly, high amounts of AGA-like proteins are secreted in the venom of two phylogenetically distant hymenopteran parasitoid wasp species, Asobara tabida (Braconidae) and Leptopilina heterotoma (Cynipidae). These venom AGAs have a similar domain organization as mammalian AGAs. They share with them key residues for autocatalysis and activity, and the mature α- and β-subunits also form an (αβ)2 structure in solution. Interestingly, only one of these AGAs subunits (α for AtAGA and β for LhAGA) is glycosylated instead of the two subunits for lysosomal human AGA (hAGA), and these glycosylations are partially resistant to PGNase F treatment. The two venom AGAs are secreted as fully activated enzymes, they have a similar aspartylglucosaminidase activity and are both also efficient asparaginases. Once AGAs are injected into the larvae of the Drosophila melanogaster host, the asparaginase activity may play a role in modulating their physiology. Altogether, our data provide new elements for a better understanding of the secretion and the role of venom AGAs as virulence factors in the parasitoid wasps' success.
Topics: Amino Acid Sequence; Animals; Aspartylglucosylaminase; Drosophila melanogaster; Models, Molecular; Sequence Alignment; Wasp Venoms; Wasps
PubMed: 28742131
DOI: 10.1371/journal.pone.0181940 -
Transplantation Mar 2006Allogeneic hematopoietic stem cell transplantation (ASCT) is a possible cure for many inherited disorders.
BACKGROUND
Allogeneic hematopoietic stem cell transplantation (ASCT) is a possible cure for many inherited disorders.
METHODS
We report 20 years of experience in 71 patients. The disorders include 7 immunodeficiencies, 21 hematological disorders, 13 histiocytic disorders, 9 mucopolysaccharoidoses, 7 metachromatic leukodystrophies (MLD), 3 adrenoleukodystrophies (ALD), 2 adrenomyeloneuropathy (AMN), 6 patients with Gaucher's disease, 1 Sandhoff's disease, and 2 patients with aspartylglucosaminuria. Their median age was 4 (0-39) years. The donors were 29 HLA-identical related, 27 matched unrelated (MUD) and 15 HLA mismatches.
RESULTS
In recipients of HLA-identical sibling grafts, none developed acute GVHD grades II-IV as against 22% in all others. The overall cumulative incidence of chronic GVHD was 17%. The 5-year survival rates were 93%, 84%, and 46% in recipients of grafts from HLA-identical siblings, MUD and HLA-mismatches, respectively. The overall 10-year survival rate was 69%. All of the surviving patients with immunodeficiencies and hemoglobinopathies are well. Four patients with Hurler's disease are also well, apart from skeletal problems. Five patients with Gaucher's disease are between 14 and 22 years after the transplant. Two infants with MLD deteriorated, a girl with the juvenile form has stable disease and one woman with the adult form has improved. Among four survivors with ALD/AMN, three are well and one has dementia. Two patients with aspartylglucosaminuria have stable disease.
CONCLUSION
In patients with inborn errors of metabolism, ASCT gives a high survival rate using HLA-matched donors. Beneficial effects are seen in those who are transplanted early.
Topics: Adolescent; Adult; Bacterial Infections; Child; Child, Preschool; Female; Graft vs Host Disease; HLA Antigens; Hematopoietic Stem Cell Transplantation; Histocompatibility; Humans; Infant; Infant, Newborn; Male; Metabolism, Inborn Errors; Neoplasms; Transplantation, Homologous; Treatment Outcome
PubMed: 16534474
DOI: 10.1097/01.tp.0000181457.43146.36 -
Epilepsia Jun 2009From the age of 24 years a young man with a definitive diagnosis of aspartylglucosaminuria (AGU) presented short-lasting sleep-related paroxysmal events characterized by...
From the age of 24 years a young man with a definitive diagnosis of aspartylglucosaminuria (AGU) presented short-lasting sleep-related paroxysmal events characterized by sudden awakening with a frightened look, hyperventilation, and complex bilateral motor activity. Nocturnal video-polysomnography recorded several events consistent with a diagnosis of hypermotor epileptic seizures. This pattern of sleep-related epileptic seizures has been reported in rare familial cases, more often in cryptogenic and symptomatic patients in the spectrum of nocturnal frontal lobe epilepsy. Epilepsy and sleep-related nonepileptic problems are common in patients with AGU, but no case of hyperkinetic nocturnal frontal lobe seizures has been reported to date. Differential diagnosis of abnormal paroxysmal motor events in sleep is frequently a challenge for the clinician: Video-polysomnographic recordings might serve to identify the possible epileptic origin of some of the excessive motor activities during sleep referred in patients with AGU.
Topics: Adult; Aspartylglucosaminuria; Humans; Male; Polysomnography; Seizures; Sleep Wake Disorders; Video Recording
PubMed: 19175389
DOI: 10.1111/j.1528-1167.2008.01991.x