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Journal of Child Neurology Apr 2021Aspartylglucosaminuria (AGU) is a recessively inherited neurodegenerative lysosomal storage disease characterized by progressive intellectual disability, skeletal... (Review)
Review
Aspartylglucosaminuria (AGU) is a recessively inherited neurodegenerative lysosomal storage disease characterized by progressive intellectual disability, skeletal abnormalities, connective tissue overgrowth, gait disturbance, and seizures followed by premature death. AGU is caused by pathogenic variants in the aspartylglucosaminidase () gene, leading to glycoasparagine accumulation and cellular dysfunction. Although more prevalent in the Finnish population, more than 30 variants have been identified worldwide. Owing to its rarity, AGU may be largely underdiagnosed. Recognition of the following early clinical features may aid in AGU diagnosis: developmental delays, hyperactivity, early growth spurt, inguinal and abdominal hernias, clumsiness, characteristic facial features, recurring upper respiratory and ear infections, tonsillectomy, multiple sets of tympanostomy tube placement, and sleep problems. Although no curative therapies currently exist, early diagnosis may provide benefit through the provision of anticipatory guidance, management of expectations, early interventions, and prophylaxis; it will also be crucial for increased clinical benefits of future AGU disease-modifying therapies.
Topics: Aspartylglucosaminuria; Humans
PubMed: 33439067
DOI: 10.1177/0883073820980904 -
AJNR. American Journal of Neuroradiology Nov 2019Aspartylglucosaminuria is a rare lysosomal storage disorder that causes slowly progressive, childhood-onset intellectual disability and motor deterioration. Previous...
BACKGROUND AND PURPOSE
Aspartylglucosaminuria is a rare lysosomal storage disorder that causes slowly progressive, childhood-onset intellectual disability and motor deterioration. Previous studies have shown, for example, hypointensity in the thalami in patients with aspartylglucosaminuria on T2WI, especially in the pulvinar nuclei. Susceptibility-weighted imaging is a neuroimaging technique that uses tissue magnetic susceptibility to generate contrast and is able to visualize iron and other mineral deposits in the brain. SWI findings in aspartylglucosaminuria have not been reported previously.
MATERIALS AND METHODS
Twenty-one patients with aspartylglucosaminuria (10 girls; 7.4-15.0 years of age) underwent 3T MR imaging. The protocol included an SWI sequence, and the images were visually evaluated. Thirteen patients (6 girls, 7.4-15.0 years of age) had good-quality SWI. Eight patients had motion artifacts and were excluded from the visual analysis. Thirteen healthy children (8 girls, 7.3-14.1 years of age) were imaged as controls.
RESULTS
We found a considerably uniform distribution of decreased signal intensity in SWI in the thalamic nuclei in 13 patients with aspartylglucosaminuria. The most evident hypointensity was found in the pulvinar nuclei. Patchy hypointensities were also found especially in the medial and anterior thalamic nuclei. Moreover, some hypointensity was noted in globi pallidi and substantia nigra in older patients. The filtered-phase images indicated accumulation of paramagnetic compounds in these areas. No abnormal findings were seen in the SWI of the healthy controls.
CONCLUSIONS
SWI indicates accumulation of paramagnetic compounds in the thalamic nuclei in patients with aspartylglucosaminuria. The finding may raise the suspicion of this rare disease in clinical practice.
Topics: Adolescent; Aspartylglucosaminuria; Brain; Child; Female; Humans; Magnetic Resonance Imaging; Male; Neuroimaging
PubMed: 31649158
DOI: 10.3174/ajnr.A6288 -
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 -
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 -
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 -
Cells Jun 2020The glycoprotein disorders are a group of lysosomal storage diseases (α-mannosidosis, aspartylglucosaminuria, β-mannosidosis, fucosidosis, galactosialidosis,... (Review)
Review
The glycoprotein disorders are a group of lysosomal storage diseases (α-mannosidosis, aspartylglucosaminuria, β-mannosidosis, fucosidosis, galactosialidosis, sialidosis, mucolipidosis II, mucolipidosis III, and Schindler Disease) characterized by specific lysosomal enzyme defects and resultant buildup of undegraded glycoprotein substrates. This buildup causes a multitude of abnormalities in patients including skeletal dysplasia, inflammation, ocular abnormalities, liver and spleen enlargement, myoclonus, ataxia, psychomotor delay, and mild to severe neurodegeneration. Pharmacological treatment options exist through enzyme replacement therapy (ERT) for a few, but therapies for this group of disorders is largely lacking. Hematopoietic cell transplant (HCT) has been explored as a potential therapeutic option for many of these disorders, as HCT introduces functional enzyme-producing cells into the bone marrow and blood along with the engraftment of healthy donor cells in the central nervous system (presumably as brain macrophages or a type of microglial cell). The outcome of HCT varies widely by disease type. We report our institutional experience with HCT as well as a review of the literature to better understand HCT and outcomes for the glycoprotein disorders.
Topics: Animals; Enzyme Replacement Therapy; Glycoproteins; Hematopoietic Stem Cell Transplantation; Humans; Lysosomal Storage Diseases
PubMed: 32517081
DOI: 10.3390/cells9061411 -
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 -
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 -
BMJ Neurology Open 2021Carlos II of Spain (1661-1700), last of the Spanish Habsburgs, was known as The 'Bewitched' due to his multiple medical issues and feeble nature. He suffered from a...
Carlos II of Spain (1661-1700), last of the Spanish Habsburgs, was known as The 'Bewitched' due to his multiple medical issues and feeble nature. He suffered from a range of ailments extending beyond the well-known Habsburg jaw, including developmental delay, intellectual disability, dysarthria, skeletal deformity, recurrent infections, epilepsy and infertility, among others. The Habsburg dynasty of Spain was characterised by marked inbreeding, and the male line died out with Carlos II. Various diagnoses have been proffered to explain Carlos II's infirmity, though none have been full satisfactory to explain the full breadth of his ailments. As illustrated here, it may be that aspartylglucosaminuria, an autosomal recessively inherited lysosomal storage disorder, can account for both the characteristic facial features and the wide variety of other features exhibited by Carlos II.
PubMed: 34632386
DOI: 10.1136/bmjno-2020-000072