A cross‐sectional natural history study of aspartylglucosaminuria
Abstract 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 cour...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-09-01
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| Series: | JIMD Reports |
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| Online Access: | https://doi.org/10.1002/jmd2.12294 |
| _version_ | 1811274090432954368 |
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| author | Kimberly Goodspeed Daniel Horton Andrea Lowden Peter V. Sguigna Timothy Booth Zhiyue J. Wang Veronica Bordes Edgar |
| author_facet | Kimberly Goodspeed Daniel Horton Andrea Lowden Peter V. Sguigna Timothy Booth Zhiyue J. Wang Veronica Bordes Edgar |
| author_sort | Kimberly Goodspeed |
| collection | DOAJ |
| description | Abstract 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, p = 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. |
| first_indexed | 2024-04-12T23:11:48Z |
| format | Article |
| id | doaj.art-51d90e9cc24f421e9a38d66848bac1f3 |
| institution | Directory Open Access Journal |
| issn | 2192-8312 |
| language | English |
| last_indexed | 2024-04-12T23:11:48Z |
| publishDate | 2022-09-01 |
| publisher | Wiley |
| record_format | Article |
| series | JIMD Reports |
| spelling | doaj.art-51d90e9cc24f421e9a38d66848bac1f32022-12-22T03:12:47ZengWileyJIMD Reports2192-83122022-09-0163542543310.1002/jmd2.12294A cross‐sectional natural history study of aspartylglucosaminuriaKimberly Goodspeed0Daniel Horton1Andrea Lowden2Peter V. Sguigna3Timothy Booth4Zhiyue J. Wang5Veronica Bordes Edgar6Department of Pediatrics University of Texas Southwestern Medical Center Dallas Texas USAChildren's Health Dallas Dallas Texas USADepartment of Pediatrics University of Texas Southwestern Medical Center Dallas Texas USADepartment of Neurology University of Texas Southwestern Medical Center Dallas Texas USAChildren's Health Dallas Dallas Texas USAChildren's Health Dallas Dallas Texas USADepartment of Pediatrics University of Texas Southwestern Medical Center Dallas Texas USAAbstract 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, p = 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.https://doi.org/10.1002/jmd2.12294AGAaspartylglucosaminuriaelectrophysiologygene transfer therapylysosomal storage disorderneuroimaging |
| spellingShingle | Kimberly Goodspeed Daniel Horton Andrea Lowden Peter V. Sguigna Timothy Booth Zhiyue J. Wang Veronica Bordes Edgar A cross‐sectional natural history study of aspartylglucosaminuria JIMD Reports AGA aspartylglucosaminuria electrophysiology gene transfer therapy lysosomal storage disorder neuroimaging |
| title | A cross‐sectional natural history study of aspartylglucosaminuria |
| title_full | A cross‐sectional natural history study of aspartylglucosaminuria |
| title_fullStr | A cross‐sectional natural history study of aspartylglucosaminuria |
| title_full_unstemmed | A cross‐sectional natural history study of aspartylglucosaminuria |
| title_short | A cross‐sectional natural history study of aspartylglucosaminuria |
| title_sort | cross sectional natural history study of aspartylglucosaminuria |
| topic | AGA aspartylglucosaminuria electrophysiology gene transfer therapy lysosomal storage disorder neuroimaging |
| url | https://doi.org/10.1002/jmd2.12294 |
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