Biochemical correlates of neuropsychiatric illness in maple syrup urine disease
Emilie R. Muelly, Gregory J. Moore, Scott C. Bunce, Julie Mack, Don C. Bigler, D. Holmes Morton, Kevin A. Strauss
Emilie R. Muelly, Gregory J. Moore, Scott C. Bunce, Julie Mack, Don C. Bigler, D. Holmes Morton, Kevin A. Strauss
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Research Article Neuroscience

Biochemical correlates of neuropsychiatric illness in maple syrup urine disease

Abstract

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. Dietary management enables survival and reduces risk of acute crises. Liver transplantation has emerged as an effective way to eliminate acute decompensation risk. Psychiatric illness is a reported MSUD complication, but has not been well characterized and remains poorly understood. 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. Compared with 26 age-matched controls, MSUD patients were at higher risk for disorders of cognition, attention, and mood. 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. Asymptomatic neonatal course and stringent longitudinal biochemical control proved fundamental to optimizing long-term mental health. Neuropsychiatric morbidity and neurochemistry were similar among transplanted and nontransplanted MSUD patients. In conclusion, amino acid dysregulation results in aberrant neural networks with neurochemical deficiencies that persist after transplant and correlate with neuropsychiatric morbidities. These findings may provide insight into general mechanisms of psychiatric illness.

Authors

Emilie R. Muelly, Gregory J. Moore, Scott C. Bunce, Julie Mack, Don C. Bigler, D. Holmes Morton, Kevin A. Strauss

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Figure 5

Theories of neurotoxic mechanisms of MSUD.

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Theories of neurotoxic mechanisms of MSUD. At the blood-brain barrier, l...
At the blood-brain barrier, leucine, which has a low Km for LAT1, saturates the transporter and blocks uptake of its competitors tyrosine, phenylalanine, tryptophan, isoleucine, histamine, valine, methionine, glutamine, and threonine. Among these are precursors for neurotransmitters (dopamine, norepinephrine, serotonin, and histamine) and S-adenosylmethionine (S-AdoMet), the brain’s major methyl donor. aKIC enters the brain via the monocarboxylate transporter (MCT) and reverses flux through cerebral transaminases (TA). This depletes brain glutamate, GABA, and glutamine while increasing production of leucine and α-ketoglutarate (aKG). Glutamate and GABA are the most abundant excitatory and inhibitory neurotransmitters, respectively, in the human brain. MSUD encephalopathy may also block oxidative phosphorylation through an as yet unknown mechanism; in vitro data has implicated aKIC-mediated inhibition of pyruvate dehydrogenase (PDH), α-ketoglutarate dehydrogenase (aKGDH), and components of the electron transport chain (ETC). Impaired mitochondrial function can interfere with the production of NAA, which therefore serves as a marker for neuronal energy production. Additionally, energy from ATP is sometimes transferred to the creaine-phosphocreatine (Cr-PCr) system for later use.