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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 -
Journal of Biomolecular Structure &... May 2024Aspartylglucosaminuria (AGU) is a lysosomal storage disorder caused by insufficient aspartylglucosaminidase (AGA) activity leading to chronic neurodegeneration. We...
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 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 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.
Topics: Molecular Dynamics Simulation; Phosphorylation; Mutation; Humans; Aspartylglucosaminuria; Aspartylglucosylaminase; Protein Conformation; Hydrogen Bonding; Structure-Activity Relationship
PubMed: 37334725
DOI: 10.1080/07391102.2023.2220798 -
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 -
Journal of Inherited Metabolic Disease Mar 2023Oligosaccharidoses, sphingolipidoses and mucolipidoses are lysosomal storage disorders (LSDs) in which defective breakdown of glycan-side chains of glycosylated proteins...
Oligosaccharidoses, sphingolipidoses and mucolipidoses are lysosomal storage disorders (LSDs) in which defective breakdown of glycan-side chains of glycosylated proteins and glycolipids leads to the accumulation of incompletely degraded oligosaccharides within lysosomes. In metabolic laboratories, these disorders are commonly diagnosed by thin-layer chromatography (TLC) but more recently also mass spectrometry-based approaches have been published. To expand the possibilities to screen for these diseases, we developed an ultra-high-performance liquid chromatography (UHPLC) with a high-resolution accurate mass (HRAM) mass spectrometry (MS) screening platform, together with an open-source iterative bioinformatics pipeline. This pipeline generates comprehensive biomarker profiles and allows for extensive quality control (QC) monitoring. Using this platform, we were able to identify α-mannosidosis, β-mannosidosis, α-N-acetylgalactosaminidase deficiency, sialidosis, galactosialidosis, fucosidosis, aspartylglucosaminuria, GM1 gangliosidosis, GM2 gangliosidosis (M. Sandhoff) and mucolipidosis II/III in patient samples. Aberrant urinary oligosaccharide excretions were also detected for other disorders, including NGLY1 congenital disorder of deglycosylation, sialic acid storage disease, MPS type IV B and GSD II (Pompe disease). For the latter disorder, we identified heptahexose (Hex7), as a potential urinary biomarker, in addition to glucose tetrasaccharide (Glc4), for the diagnosis and monitoring of young onset cases of Pompe disease. Occasionally, so-called "neonate" biomarker profiles were observed in young patients, which were probably due to nutrition. Our UHPLC/HRAM-MS screening platform can easily be adopted in biochemical laboratories and allows for simple and robust screening and straightforward interpretation of the screening results to detect disorders in which aberrant oligosaccharides accumulate.
Topics: Humans; Chromatography, High Pressure Liquid; Glycogen Storage Disease Type II; Lysosomal Storage Diseases; Mucolipidoses; Tandem Mass Spectrometry; Oligosaccharides; Mucopolysaccharidosis IV
PubMed: 36752951
DOI: 10.1002/jimd.12597 -
Zhonghua Yi Xue Yi Chuan Xue Za Zhi =... Jan 2023To explore the genetic basis for a child with Aspartylglucosaminuria (AGU).
OBJECTIVE
To explore the genetic basis for a child with Aspartylglucosaminuria (AGU).
METHODS
Clinical data of the patient was analyzed. The child was subjected to trio-whole exome sequencing (WES) and copy number variation sequencing (CNV-seq), and candidate variant was verified by Sanger sequencing.
RESULTS
The child was found to harbor homozygous c.319C>T (p.Arg107*) nonsense variant of the AGA gene, for which both of his parents were heterozygous carriers. No abnormality was found by CNV-seq analysis. The c.319C>T (p.Arg107*) variant was not found in population database, HGMD and other databases. Based on guidelines of the American College of Medical Genetics and Genomics, the variant was predicted to be pathogenic (PVS1+PM2+PP3).
CONCLUSION
The c.319C>T variant of the AGA gene probably underlay the autosomal recessive AGU in this child. Above finding has enabled genetic counseling and prenatal diagnosis for his parents.
Topics: Female; Pregnancy; Humans; Child; Aspartylglucosaminuria; DNA Copy Number Variations; Genetic Counseling; Genomics; Heterozygote; Mutation
PubMed: 36585008
DOI: 10.3760/cma.j.cn511374-20220107-00015 -
AJNR. American Journal of Neuroradiology Jan 2023We investigated global and local properties of the structural brain connectivity networks in aspartylglucosaminuria, an autosomal recessive and progressive...
BACKGROUND AND PURPOSE
We investigated global and local properties of the structural brain connectivity networks in aspartylglucosaminuria, an autosomal recessive and progressive neurodegenerative lysosomal storage disease. Brain connectivity in aspartylglucosaminuria has not been investigated before, but previous structural MR imaging studies have shown brain atrophy, delayed myelination, and decreased thalamic and increased periventricular WM T2 signal intensity.
MATERIALS AND METHODS
We acquired diffusion MR imaging and T1-weighted data from 12 patients with aspartylglucosaminuria (mean age, 23 [SD, 8] years; 5 men), and 30 healthy controls (mean age, 25 [SD, 10] years; 13 men). We performed whole-brain constrained spherical deconvolution tractography, which enables the reconstruction of neural tracts through regions with complex fiber configurations, and used graph-theoretical analysis to investigate the structural brain connectivity networks.
RESULTS
The integration of the networks was decreased, as demonstrated by a decreased normalized global efficiency and an increased normalized characteristic path length. In addition, the average strength of the networks was decreased. In the local analyses, we found decreased strength in 11 nodes, including, for example, the right thalamus, right putamen, and, bilaterally, several occipital and temporal regions.
CONCLUSIONS
We found global and local structural connectivity alterations in aspartylglucosaminuria. Biomarkers related to the treatment efficacy are needed, and brain network properties may provide the means for long term follow-up.
Topics: Male; Humans; Young Adult; Adult; Case-Control Studies; Aspartylglucosaminuria; Brain; Magnetic Resonance Imaging; Thalamus
PubMed: 36549851
DOI: 10.3174/ajnr.A7745 -
Brain Sciences Nov 2022Magnetic resonance (MR) imaging data can be used to develop computer-assisted diagnostic tools for neurodegenerative diseases such as aspartylglucosaminuria (AGU) and...
Magnetic resonance (MR) imaging data can be used to develop computer-assisted diagnostic tools for neurodegenerative diseases such as aspartylglucosaminuria (AGU) and other lysosomal storage disorders. MR images contain features that are suitable for the classification and differentiation of affected individuals from healthy persons. Here, comparisons were made between MRI features extracted from different types of magnetic resonance images. Random forest classifiers were trained to classify AGU patients ( = 22) and healthy controls ( = 24) using volumetric features extracted from T1-weighted MR images, the zone variance of gray level size zone matrix (GLSZM) calculated from magnitude susceptibility-weighted MR images, and the caudate-thalamus intensity ratio computed from T2-weighted MR images. The leave-one-out cross-validation and area under the receiver operating characteristic curve were used to compare different models. The left-right-averaged, normalized volumes of the 25 nuclei of the thalamus and the zone variance of the thalamus demonstrated equal and excellent performance as classifier features for binary organization between AGU patients and healthy controls. Our findings show that texture-based features of susceptibility-weighted images and thalamic volumes can differentiate AGU patients from healthy controls with a very low error rate.
PubMed: 36358448
DOI: 10.3390/brainsci12111522 -
JIMD Reports Sep 2022Aspartylglucosaminuria (AGU) is a rare lysosomal storage disorder that causes stagnation of development in adolescence and neurodegeneration in early adulthood....
Aspartylglucosaminuria (AGU) is a rare lysosomal storage disorder that causes stagnation of development in adolescence and neurodegeneration in early adulthood. Precision therapies, including gene transfer therapy, are in development with a goal of taking advantage of the slow clinical course. Understanding of disease natural history and identification of disease-relevant biomarkers are important steps in clinical trial readiness. We describe the clinical features of a diverse population of patients with AGU, including potential imaging and electrophysiological biomarkers. This is a single-center, cross-sectional study of the clinical, neuropsychological, electrophysiological, and imaging characteristics of AGU. A comprehensive assessment of eight participants (5 Non-Finnish) revealed a mean non-verbal IQ (NVIQ) of 70.25 ± 10.33 which decreased with age (rs = -0.85, = 0.008). All participants demonstrated deficits in communication and gross/fine motor dysfunction. Auditory and visual evoked potentials demonstrated abnormalities in one or both modalities in 7 of 8 subjects, suggesting sensory pathway dysfunction. Brain imaging demonstrated T2 FLAIR hypointensity in the pulvinar nuclei and cerebral atrophy, as previously shown in the Finnish AGU population. Magnetic resonance spectroscopy (MRS) showed a 5.1 ppm peak corresponding to the toxic substrate (GlcNAc-Asn), which accumulates in AGU. Our results showed there was no significant difference between Finnish and Non-Finnish patients, and performance on standardized cognitive and motor testing was similar to prior studies. Age-related changes on functional assessments and disease-relevant abnormalities on surrogate biomarkers, such as MRS, could be used as outcome measures in a clinical trial.
PubMed: 36101820
DOI: 10.1002/jmd2.12294 -
Cells Oct 2021Splicing defects caused by mutations in the consensus sequences at the borders of introns and exons are common in human diseases. Such defects frequently result in a...
Towards Splicing Therapy for Lysosomal Storage Disorders: Methylxanthines and Luteolin Ameliorate Splicing Defects in Aspartylglucosaminuria and Classic Late Infantile Neuronal Ceroid Lipofuscinosis.
Splicing defects caused by mutations in the consensus sequences at the borders of introns and exons are common in human diseases. Such defects frequently result in a complete loss of function of the protein in question. Therapy approaches based on antisense oligonucleotides for specific gene mutations have been developed in the past, but they are very expensive and require invasive, life-long administration. Thus, modulation of splicing by means of small molecules is of great interest for the therapy of genetic diseases resulting from splice-site mutations. Using minigene approaches and patient cells, we here show that methylxanthine derivatives and the food-derived flavonoid luteolin are able to enhance the correct splicing of the AGA mRNA with a splice-site mutation c.128-2A>G in aspartylglucosaminuria, and result in increased AGA enzyme activity in patient cells. Furthermore, we also show that one of the most common disease causing gene variants in classic late infantile neuronal ceroid lipofuscinosis may also be amenable to splicing modulation using similar substances. Therefore, our data suggest that splice-modulation with small molecules may be a valid therapy option for lysosomal storage disorders.
Topics: Amino Acid Sequence; Aspartylglucosaminuria; Aspartylglucosylaminase; Base Sequence; Fibroblasts; HEK293 Cells; Homozygote; Humans; Luciferases, Firefly; Luteolin; Mutation; Neuronal Ceroid-Lipofuscinoses; RNA Splice Sites; RNA Splicing; RNA Splicing Factors; RNA, Messenger; Tripeptidyl-Peptidase 1; Xanthines
PubMed: 34831035
DOI: 10.3390/cells10112813