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.

Figure 1. Glutamate (in mmol/kg wet weight, ww) in the prefrontal and anterior cingulate cortices (violet) and basal ganglia (blue) region inversely correlated with ambient plasma leucine (left panel) and the calculated cerebral leucine influx (right panel) in MSUD patients on diet (circles) or after liver transplantation (diamonds).

Control subjects are represented as gray squares. The 2 MSUD diet patients who demonstrate relatively higher cortical glutamate levels despite having the highest estimated leucine influx are brothers (circled in red).

Figure 2. Cumulative prevalence and neonatal risks associated with neuropsychiatric outcome in classical MSUD patients.

The cumulative lifetime incidence of mental illness (depression, anxiety disorders, ADHD) among all MSUD patients reached 83% by age 36 (A). Neonatal encephalopathy was a strong predictor of mood disorders, but not mental retardation or ADHD, later in life (B). *P < 0.05.

Figure 3. Clinical and neurochemical correlates of IQ in classical MSUD patients.

There was an inverse correlation between IQ and age among the subgroup of Mennonite patients (A). An inverse correlation between full scale IQ and lifetime plasma leucine/valine ratio was found (B). Cerebral metabolites, such as basal ganglia N-acetylasparate, also correlated with various IQ measures (C). Symbols: Mennonite MSUD diet (violet circles); Mennonite MSUD transplant (blue diamonds); non-Mennonite MSUD diet (orange circles); non-Mennonite transplant (yellow diamonds); control subjects, (gray shaded areas [mean ± SD] or gray squares).

Figure 4. 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).

Figure 5. Theories of neurotoxic mechanisms of MSUD.

At the blood-brain barrier, leucine, which has a low K_m 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.

Figure 6. Cerebral atrophy in MSUD.

A series of T2-weighted axial images from an MSUD participant who experienced poor metabolic control early in life (upper panel) and an age-matched control (lower panel) show the cerebral atrophy observed in some older patients who experienced prolonged amino acid imbalances during infancy or long periods of poor longitudinal metabolic control. There is a general loss of brain tissue at every level of the neturaxis, visible as thinner cortical gyri and cerebellar fossa, prominent sulci, and expansion of the perivascular spaces, particularly evident near the cortical surface and temporal lobes.

Figure 7. Historical improvement in cerebral valine nutrition.

Improved dietary management has resulted in a trend of an increasing ratio of valine (val) to the other BCAAs (isoleucine, leucine, allo-isoleucine [allo]) competing for transport across the blood brain barrier. *P < 0.05. Error bars represent mean ± SD.

Figure 8. MRS methods.

Regions of interest for quantitative MRS were placed in the left basal ganglia (A, left), prefrontal and anterior cingulate cortices (middle), and right parietal centrum semiovale white matter (right). Sample resulting MRS spectra from the anterior cingulated cortex of a control (B, left) and MSUD patient (B, right) demonstrate a relative decrease in glutamate (Glu), creatine (Cre), and NAA peaks. The choline peak (Cho) is also labeled in the spectra from the MSUD patient.