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 4

Clinical and neurochemical correlates of ADHD symptoms in MSUD patients.

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Clinical and neurochemical correlates of ADHD symptoms in MSUD patients....
ADHD was inversely correlated to age (A) and directly related to the lifetime plasma leucine/tyrosine ratio (B). Plasma leucine at the time of the study does not correlate with ADHD symptoms scores. However, an interaction exists between plasma leucine and history of an ADHD diagnosis in predicting total ADHD ratings at the time of the study, such that in those patients who have ever had a diagnosis of ADHD, higher leucine levels corresponded with higher symptom ratings (C). Severity of inattention symptoms correlated with several metabolites, such as prefrontal and anterior cingulate (ACC) cortical NAA (D). Symbols: Mennonite MSUD diet (violet circles); Mennonite MSUD transplant (blue diamonds); non-Mennonite MSUD diet (yellow circles); non-Mennonite transplant (yellow diamonds); no ADHD (yellow squares); control subjects (gray shaded areas [mean ± SD] or gray squares).