Relationship between longitudinal changes in neuropsychological outcome and disease biomarkers in urea cycle disorders

Urea Cycle Disorders Consortium

doi:10.1038/s41390-023-02722-y

Relationship between longitudinal changes in neuropsychological outcome and disease biomarkers in urea cycle disorders

Urea Cycle Disorders Consortium

Pediatrics - Genetics and Metabolism

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

Background: Urea cycle disorders (UCDs) cause impaired conversion of waste nitrogen to urea leading to rise in glutamine and ammonia. Elevated ammonia and glutamine have been implicated in brain injury. This study assessed relationships between biomarkers of metabolic control and long-term changes in neuropsychological test scores in participants of the longitudinal study of UCDs. The hypothesis was that elevated ammonia and glutamine are associated with neuropsychological impairment. Methods: Data from 146 participants who completed 2 neuropsychological assessments were analyzed. Neuropsychological tests that showed significant changes in scores over time were identified and associations between score change and interim metabolic biomarker levels were investigated. Results: Participants showed a significant decrease in performance on visual motor integration (VMI) and verbal learning immediate-recall. A decrease in scores was associated with experiencing interim hyperammonemic events (HAE) and frequency of HAE. Outside of HAE there was a significant association between median ammonia levels ≥50µmol/L and impaired VMI. Conclusion: VMI and memory encoding are specifically affected in UCDs longitudinally, indicating that patients experience difficulties when required to integrate motor and visual functions and learn new information. Only ammonia biomarkers showed a significant association with impairment. Preventing HAE and controlling ammonia levels is key in UCD management. Impact: The Beery-Buktenica Developmental Test of Visual-Motor Integration (Beery VMI) and List A Trial 5 of the California Verbal Learning Test (CVLT) may be good longitudinal biomarkers of treatment outcome in urea cycle disorders (UCD).This is the first report of longitudinal biomarkers for treatment outcome in UCD.These two biomarkers of outcome may be useful for clinical trials assessing new treatments for UCD. These results will also inform educators how to design interventions directed at improving learning in individuals with UCDs.

Original language	English (US)
Pages (from-to)	2005-2015
Number of pages	11
Journal	Pediatric Research
Volume	94
Issue number	6
DOIs	https://doi.org/10.1038/s41390-023-02722-y
State	Published - Dec 2023

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© 2023, The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.

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@article{92459e70834443beb1b555d0aa63d6ee,

title = "Relationship between longitudinal changes in neuropsychological outcome and disease biomarkers in urea cycle disorders",

abstract = "Background: Urea cycle disorders (UCDs) cause impaired conversion of waste nitrogen to urea leading to rise in glutamine and ammonia. Elevated ammonia and glutamine have been implicated in brain injury. This study assessed relationships between biomarkers of metabolic control and long-term changes in neuropsychological test scores in participants of the longitudinal study of UCDs. The hypothesis was that elevated ammonia and glutamine are associated with neuropsychological impairment. Methods: Data from 146 participants who completed 2 neuropsychological assessments were analyzed. Neuropsychological tests that showed significant changes in scores over time were identified and associations between score change and interim metabolic biomarker levels were investigated. Results: Participants showed a significant decrease in performance on visual motor integration (VMI) and verbal learning immediate-recall. A decrease in scores was associated with experiencing interim hyperammonemic events (HAE) and frequency of HAE. Outside of HAE there was a significant association between median ammonia levels ≥50µmol/L and impaired VMI. Conclusion: VMI and memory encoding are specifically affected in UCDs longitudinally, indicating that patients experience difficulties when required to integrate motor and visual functions and learn new information. Only ammonia biomarkers showed a significant association with impairment. Preventing HAE and controlling ammonia levels is key in UCD management. Impact: The Beery-Buktenica Developmental Test of Visual-Motor Integration (Beery VMI) and List A Trial 5 of the California Verbal Learning Test (CVLT) may be good longitudinal biomarkers of treatment outcome in urea cycle disorders (UCD).This is the first report of longitudinal biomarkers for treatment outcome in UCD.These two biomarkers of outcome may be useful for clinical trials assessing new treatments for UCD. These results will also inform educators how to design interventions directed at improving learning in individuals with UCDs.",

author = "{Urea Cycle Disorders Consortium} and Uta Lichter-Konecki and Sanz, {Jacqueline H.} and {Ah Mew}, Nicholas and Baumgartner, {Matthias R.} and Bedoyan, {Jirair K.} and Gerard Berry and Berry, {Susan A.} and Peter Burgard and Lindsay Burrage and Curtis Coughlin and Diaz, {George A.} and Gregory Enns and Gallagher, {Renata C.} and Andrea Gropman and Harding, {Cary O.} and Hoffmann, {Georg F.} and {Le Mons}, Cynthia and McCandless, {Shawn E.} and Merritt, {J. Lawrence} and Nagamani, {Sandesh C.S.} and Andreas Schulze and Jennifer Seminara and Tamar Stricker and Susan Waisbren and Derek Wong and Marc Yudkoff and Robert McCarter",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.",

year = "2023",

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doi = "10.1038/s41390-023-02722-y",

language = "English (US)",

volume = "94",

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TY - JOUR

T1 - Relationship between longitudinal changes in neuropsychological outcome and disease biomarkers in urea cycle disorders

AU - Urea Cycle Disorders Consortium

AU - Lichter-Konecki, Uta

AU - Sanz, Jacqueline H.

AU - Ah Mew, Nicholas

AU - Baumgartner, Matthias R.

AU - Bedoyan, Jirair K.

AU - Berry, Gerard

AU - Berry, Susan A.

AU - Burgard, Peter

AU - Burrage, Lindsay

AU - Coughlin, Curtis

AU - Diaz, George A.

AU - Enns, Gregory

AU - Gallagher, Renata C.

AU - Gropman, Andrea

AU - Harding, Cary O.

AU - Hoffmann, Georg F.

AU - Le Mons, Cynthia

AU - McCandless, Shawn E.

AU - Merritt, J. Lawrence

AU - Nagamani, Sandesh C.S.

AU - Schulze, Andreas

AU - Seminara, Jennifer

AU - Stricker, Tamar

AU - Waisbren, Susan

AU - Wong, Derek

AU - Yudkoff, Marc

AU - McCarter, Robert

PY - 2023/12

Y1 - 2023/12

N2 - Background: Urea cycle disorders (UCDs) cause impaired conversion of waste nitrogen to urea leading to rise in glutamine and ammonia. Elevated ammonia and glutamine have been implicated in brain injury. This study assessed relationships between biomarkers of metabolic control and long-term changes in neuropsychological test scores in participants of the longitudinal study of UCDs. The hypothesis was that elevated ammonia and glutamine are associated with neuropsychological impairment. Methods: Data from 146 participants who completed 2 neuropsychological assessments were analyzed. Neuropsychological tests that showed significant changes in scores over time were identified and associations between score change and interim metabolic biomarker levels were investigated. Results: Participants showed a significant decrease in performance on visual motor integration (VMI) and verbal learning immediate-recall. A decrease in scores was associated with experiencing interim hyperammonemic events (HAE) and frequency of HAE. Outside of HAE there was a significant association between median ammonia levels ≥50µmol/L and impaired VMI. Conclusion: VMI and memory encoding are specifically affected in UCDs longitudinally, indicating that patients experience difficulties when required to integrate motor and visual functions and learn new information. Only ammonia biomarkers showed a significant association with impairment. Preventing HAE and controlling ammonia levels is key in UCD management. Impact: The Beery-Buktenica Developmental Test of Visual-Motor Integration (Beery VMI) and List A Trial 5 of the California Verbal Learning Test (CVLT) may be good longitudinal biomarkers of treatment outcome in urea cycle disorders (UCD).This is the first report of longitudinal biomarkers for treatment outcome in UCD.These two biomarkers of outcome may be useful for clinical trials assessing new treatments for UCD. These results will also inform educators how to design interventions directed at improving learning in individuals with UCDs.

AB - Background: Urea cycle disorders (UCDs) cause impaired conversion of waste nitrogen to urea leading to rise in glutamine and ammonia. Elevated ammonia and glutamine have been implicated in brain injury. This study assessed relationships between biomarkers of metabolic control and long-term changes in neuropsychological test scores in participants of the longitudinal study of UCDs. The hypothesis was that elevated ammonia and glutamine are associated with neuropsychological impairment. Methods: Data from 146 participants who completed 2 neuropsychological assessments were analyzed. Neuropsychological tests that showed significant changes in scores over time were identified and associations between score change and interim metabolic biomarker levels were investigated. Results: Participants showed a significant decrease in performance on visual motor integration (VMI) and verbal learning immediate-recall. A decrease in scores was associated with experiencing interim hyperammonemic events (HAE) and frequency of HAE. Outside of HAE there was a significant association between median ammonia levels ≥50µmol/L and impaired VMI. Conclusion: VMI and memory encoding are specifically affected in UCDs longitudinally, indicating that patients experience difficulties when required to integrate motor and visual functions and learn new information. Only ammonia biomarkers showed a significant association with impairment. Preventing HAE and controlling ammonia levels is key in UCD management. Impact: The Beery-Buktenica Developmental Test of Visual-Motor Integration (Beery VMI) and List A Trial 5 of the California Verbal Learning Test (CVLT) may be good longitudinal biomarkers of treatment outcome in urea cycle disorders (UCD).This is the first report of longitudinal biomarkers for treatment outcome in UCD.These two biomarkers of outcome may be useful for clinical trials assessing new treatments for UCD. These results will also inform educators how to design interventions directed at improving learning in individuals with UCDs.

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U2 - 10.1038/s41390-023-02722-y

DO - 10.1038/s41390-023-02722-y

M3 - Article

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AN - SCOPUS:85165005371

SN - 0031-3998

VL - 94

SP - 2005

EP - 2015

JO - Pediatric Research

JF - Pediatric Research

IS - 6

ER -

Relationship between longitudinal changes in neuropsychological outcome and disease biomarkers in urea cycle disorders

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