In proximal urea cycle disorders (UCD), particularlyornithine transcarbamylase deficiency (OTCD), hyperammonemia (HA) causes increased brain glutamine (Gin) which perturbation is thoughtto be at the core of the neurological injury. In contrast, in distal UCD such as citrullinemia(argininosuccinatesynthetase deficiency; (ASSD) and argininosuccinicaciduria(argininosuccinatelyase deficiency); (ASLD) cognitive impairment and neuropsychiatric disease are common even in the absence of acute HA. As a consequence, both citrulline and argininosuccinate (ASA) or their metabolic products have been implicated as neurotoxic. In this project we will use state-of- the-art neuroimaging and neuropsychological methods to investigate whether patients with OTCD have chronically elevated brain Gin and reduced myo-inositol (ml) levels that correlate with regional brain structural abnormalities and neurocognitive dysfunction. We will further investigate whether during an acute episode of HA elevated brain Gin and decreased ml levels correlate with the magnitude of cytotoxic edema and whether a Gln/ml ratio threshold can be identified at which the cytotoxic edema is followed by cell loss. Finally, will investigate whether regions of brain damage in ASSD and/or ASLD are distinct from those in OTCD and compare brain Gin levels in ASSD and ASLD in the absence of HA to those in OTCD. We will also seek to determine if brain citrulline and ASA can be identified in the brains of patients with distal UCD and whether they correlate with brain abnormalities seen in MRI and neuropsychological testing. This project will elucidate the chronology of brain pathology both in acute hyperammonemia and chronic UCD and whether, proximal and distal UCD differ in their pathophysiology of brain damage.
As treatment for UCD has moved from ensuring survival to diminishing morbidity the major recognized adverse outcome is neurocognitive impairment. This study seeks to understand the pathophysiology of brain damage in proximal and distal UCD, hypothesizing that different outcomes in these disorders may relate to different metabolic accumulations. The results of this study may lead to new approaches to neuroprotection in UCD.
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