![]() ![]() Transaminases in brain tissue normally convert leucine to α-ketoglutarate to supply nitrogen to the cerebral glutamate pool ( 6, 7). ![]() Glutamate is an important metabolic currency that is used as a neurotransmitter as well as a source of energy. Accumulation of aKIC favors synthesis of leucine in the bidirectional transaminase reaction, consuming glutamate. Hyperleucinemia inhibits the transport of tyrosine, tryptophan, and other essential amino acids across the blood-brain barrier and thereby limits substrate availability for cerebral catecholamine, serotonin, and protein synthesis. In MSUD, branched chain ketoacid metabolism is blocked by a dysfunctional BCKDH, causing concentrations of upstream aKIC and leucine to increase. Proposed mechanisms of neurotoxicity include unbalanced cerebral essential amino acid uptake, neurotransmitter deficiencies, energy deprivation, and osmotic dysregulation. Although liver transplantation has proven highly effective for preventing acute crises, available evidence suggests it may not improve intelligence quotient (IQ) or reverse psychiatric disease ( 4, 5).Ĭhronic neuropsychiatric sequelae of MSUD are likely caused by several interacting mechanisms also thought to be responsible for acute neurotoxicity. However, anecdotal reports suggest that aging MSUD patients are at high risk for chronic neuropsychiatric problems such as attention deficit disorder, depression, and anxiety ( 1). Mental health outcomes and their relation to treatment variables have not been fully characterized in this population. Liver transplantation has recently emerged as an effective means to eliminate metabolic volatility and the risk of cerebral edema ( 3).Īs treatment for MSUD improves, survival improves in parallel, and physicians now manage a growing number of adolescents and adults with classical MSUD. After the neonatal period, careful dietary management limits episodic decompensations to a variable extent, improves amino acid nutrition, and greatly reduces morbidity and mortality ( 2). If not appropriately diagnosed and treated, rapid elevation of circulating leucine and its ketoacid, α-ketoisocaproate (aKIC), cause encephalopathy and life-threatening brain swelling ( 1). Patients with the most severe form, classical MSUD, may appear normal at birth, but develop acute metabolic decompensation within the first weeks of life. One such condition, branched chain ketoacid dehydrogenase (BCKDH) deficiency, also known as maple syrup urine disease (MSUD), leads to accumulation of branched chain amino acids (BCAAs) (leucine, isoleucine, and valine) and their derivative α-ketoacids in blood and tissues. Hereditary disorders that cause neuropsychiatric sequelae are a window into the biological foundations of mental illness. These findings may provide insight into general mechanisms of psychiatric illness. In conclusion, amino acid dysregulation results in aberrant neural networks with neurochemical deficiencies that persist after transplant and correlate with neuropsychiatric morbidities. Neuropsychiatric morbidity and neurochemistry were similar among transplanted and nontransplanted MSUD patients. Asymptomatic neonatal course and stringent longitudinal biochemical control proved fundamental to optimizing long-term mental health. Using quantitative proton magnetic resonance spectroscopy, we found lower brain glutamate, N-acetylaspartate (NAA), and creatine concentrations in MSUD patients, which correlated with specific neuropsychiatric outcomes. ![]() Compared with 26 age-matched controls, MSUD patients were at higher risk for disorders of cognition, attention, and mood. We report the prevalence and characteristics of neuropsychiatric problems among 37 classical MSUD patients (ages 5–35 years, 26 on dietary therapy, 11 after liver transplantation) and explore their underlying mechanisms. Psychiatric illness is a reported MSUD complication, but has not been well characterized and remains poorly understood. Liver transplantation has emerged as an effective way to eliminate acute decompensation risk. Dietary management enables survival and reduces risk of acute crises. Maple syrup urine disease (MSUD) is an inherited disorder of branched chain amino acid metabolism presenting with neonatal encephalopathy, episodic metabolic decompensation, and chronic amino acid imbalances. ![]()
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