Reduced Functional Connectivity of Default Mode and Set-Maintenance Networks in Ornithine Transcarbamylase Deficiency

Pacheco‐Colón, Ileana; Washington, Stuart D.; Sprouse, Courtney; Helman, Guy; Gropman, Andrea; VanMeter, John W.

doi:10.1371/journal.pone.0129595

Cited by 4 publications

(7 citation statements)

References 54 publications

(79 reference statements)

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“…In agreement with these reports, our group has identified that patients with distal UCD (where ammonia levels are not as elevated as in proximal disorders) have a high frequency of epilepsy and cognitive dysfunction, raising the possibility that seizures may be associated with other biochemical abnormalities in distal UCD [36,71]. Additionally, we have shown that disrupted neural networks underlying working memory are a consistent finding in UCD patients with mild as well as severe symptoms [25,46]. These studies strengthen the importance of understanding the incidence/prevalence of epilepsy in patients with UCDs and if and how this may affect later cognitive function.…”

Section: Seizures In Ucdsupporting

confidence: 84%

“…The neuroimaging/neurocognitive studies we performed as part of the UCDC focused on adolescents and adults with OTCD. Our collective studies demonstrated that OTCD heterozygous females have changes in function of the prefrontal cortex (PFC) in association with an altered neurocognitive profile in working memory, executive functioning, and attention [46]. fMRI can allow us to understand how the brain constructs neural networks to perform cognitive tasks, probe how these networks are altered in brain disorders, and allow us to follow recovery.…”

Section: How Can Neuroimaging Help Us Probe Markers Of Neurological Dmentioning

confidence: 99%

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Emerging Knowledge From Noninvasive Imaging Studies: Is Ammonia Control Enough?

Gropman¹

2020

Cellular Metabolism and Related Disorders

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Multiple lines of research suggest that ammonia is harmful to the brain if the levels remain elevated for extended periods of time. Several decades ago, there was no testing or standard of care to monitor the effect of hyperammonemia (HA) on neurological function in urea cycle disorders (UCD), and the timing of HA encephalopathy is still not clear. Magnetic resonance imaging (MRI) was not done routinely, if at all, so it was not known what changes were occurring in the brain, during and after recovery from HA. Decades ago, a diagnosis of a UCD meant severe disability and early death. Earlier diagnosis, improved management, and nitrogen scavenger therapy have improved the lives and life span of patients with UCD. However, many patients suffer from learning difficulties under the umbrella "executive function" which comprises neurologically based skills involving mental control and self-regulation. The general agreement of the core elements of executive functions includes inhibition, working memory, and cognitive flexibility and is necessary in development of skills in reasoning, fluid intelligence, problem-solving, and planning. Our research focuses on the use of noninvasive neuroimaging coupled with neuropsychological testing to understand the complex relationship between ammonia, glutamine, cognitive function, seizures, and specifically impact on development of working memory.

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Section: Seizures In Ucdsupporting

confidence: 84%

Section: How Can Neuroimaging Help Us Probe Markers Of Neurological Dmentioning

confidence: 99%

Emerging Knowledge From Noninvasive Imaging Studies: Is Ammonia Control Enough?

Gropman¹

2020

Cellular Metabolism and Related Disorders

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“…Internodal functional connectivity in the default mode network (DMN) and set-maintenance network (SMN) is reduced in patients with partial OTCD compared to controls, most likely due to HA-related white matter damage (Pacheco-Colón , et al, 2015). Because several of the affected areas are involved in executive functioning, it is postulated that this reduced connectivity may be an underlying cause of the deficits OTCD patients display in this cognitive domain.…”

Section: What Are the Neuroimaging Abnormalities In Ucd And How Can Nmentioning

confidence: 99%

“…Additionally, the brains of individuals with OTCD show alterations in functional connectivity at rest. Internodal functional connectivity in the default mode network (DMN) and set-maintenance network (SMN) is reduced in patients with partial OTCD compared to controls, most likely due to HArelated white matter damage (Pacheco-Colón et al 2015).…”

Section: Introductionmentioning

confidence: 99%

Improving long term outcomes in urea cycle disorders‐report from the Urea Cycle Disorders Consortium

Waisbren

Gropman

Batshaw

2016

J of Inher Metab Disea

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The Urea Cycle Disorders Consortium (UCDC) has conducted, beginning in 2006, a longitudinal study (LS) of 8 enzyme deficiencies/transporter defects associated with the urea cycle. These include N-acetylglutamate synthase deficiency (NAGSD); Carbamyl phosphate synthetase 1 deficiency (CPS1D); Ornithine transcarbamylase deficiency (OTCD); Argininosuccinate synthetase deficiency (ASSD) (Citrullinemia); Argininosuccinate lyase deficiency (ASLD) (Argininosuccinic aciduria); Arginase deficiency (ARGD, Argininemia); Hyperornithinemia, hyperammonemia, homocitrullinuria (HHH) syndrome (or mitochondrial ornithine transporter 1 deficiency [ORNT1D]); and Citrullinemia type II (mitochondrial aspartate/glutamate carrier deficiency [CITRIN]). There were 678 UCD patients enrolled in 14 sites in the U.S., Canada and Europe at the writing of this paper. This review summarizes findings of the consortium related to outcome, focusing primarily on neuroimaging findings and neurocognitive function. Neuroimaging studies in late onset OTCD offered evidence that brain injury caused by biochemical dysregulation may impact functional neuroanatomy serving working memory processes, an important component of executive function and regulation. Additionally, there were alteration in white mater microstructure and functional connectivity at rest. Intellectual manifestations in OTCD and other urea cycle disorders (UCD) vary. However, when neuropsychological deficits occur, they tend to be more prominent in motor/performance areas on both intelligence tests and other measures. In some disorders, adults performed significantly less well than younger patients. Further longitudinal follow-up will reveal whether this is due to declines throughout life or to improvements in diagnostics (especially newborn screening) and treatments in the younger generation of patients.

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“…Episodes of HA cause injury to the brain's white matter. We and others have shown that even "asymptomatic" OTCD is associated with an altered neurocognitive profile in an array of cognitive subdomains based in the prefrontal cortex (PFC), such as working memory, executive cognition and attention [7][8][9]. These deficits contribute significantly to disability.…”

Section: Introductionmentioning

confidence: 99%

Brain Biomarkers of Long-Term Outcome of Neonatal Onset Urea Cycle Disorder

Mourad

Häberle

Whitehead

et al. 2016

IJNS

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Urea cycle disorders (UCDs) are common inborn errors of metabolism, with an incidence of one in 30,000 births. They are caused by deficiencies in any of six enzymes and two carrier proteins, the most common being Ornithine Transcarbamylase Deficiency (OTCD). OTCD results in impairment to excrete nitrogen, causing toxic buildup of ammonia with resultant encephalopathy. Hyperammonemia (HA) induces the conversion of glutamate to glutamine in the brain. Excess glutamine in the brain causes osmotic changes, cerebral edema, changes in astrocyte morphology, and cell death. Acute symptoms of HA include vomiting, hyperventilation, seizures, and irritability. Long-term neurological effects include deficits in working memory and executive function. To date, there are no predictors of prognosis of infants with neonatal onset OTCD outside of the plasma ammonia level at presentation and duration of a hyperammonemic coma. We provide a comprehensive analysis of a 16-year-old male with neonatal onset of OTCD as an example of how brain biomarkers may be useful to monitor disease course and outcome. This male presented at 8 days of life with plasma ammonia and glutamine of 677 and 4024 micromol/L respectively, and was found to have a missense mutation in Exon 4 (p. R129H). Treatment included protein restriction, sodium benzoate, and citrulline, arginine, and iron. Despite compliance, he suffered recurrent acute hyperammonemic episodes triggered by infections or catabolic stressors. We discuss the long-term effects of the hyperammonemic episodes by following MRI-based disease biomarkers.

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Reduced Functional Connectivity of Default Mode and Set-Maintenance Networks in Ornithine Transcarbamylase Deficiency

Cited by 4 publications

References 54 publications

Emerging Knowledge From Noninvasive Imaging Studies: Is Ammonia Control Enough?

Emerging Knowledge From Noninvasive Imaging Studies: Is Ammonia Control Enough?

Improving long term outcomes in urea cycle disorders‐report from the Urea Cycle Disorders Consortium

Brain Biomarkers of Long-Term Outcome of Neonatal Onset Urea Cycle Disorder

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