Hereditary disorders that cause neuropsychiatric sequelae are a window into the biological foundations of mental illness. 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. Patients with the most severe form, classical MSUD, may appear normal at birth, but develop acute metabolic decompensation within the first weeks of life. 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
). 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
). Liver transplantation has recently emerged as an effective means to eliminate metabolic volatility and the risk of cerebral edema (3
As treatment for MSUD improves, survival improves in parallel, and physicians now manage a growing number of adolescents and adults with classical MSUD. Mental health outcomes and their relation to treatment variables have not been fully characterized in this population. 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
). 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
Chronic neuropsychiatric sequelae of MSUD are likely caused by several interacting mechanisms also thought to be responsible for acute neurotoxicity. Proposed mechanisms of neurotoxicity include unbalanced cerebral essential amino acid uptake, neurotransmitter deficiencies, energy deprivation, and osmotic dysregulation. In MSUD, branched chain ketoacid metabolism is blocked by a dysfunctional BCKDH, causing concentrations of upstream aKIC and leucine to increase. 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. Accumulation of aKIC favors synthesis of leucine in the bidirectional transaminase reaction, consuming glutamate. Glutamate is an important metabolic currency that is used as a neurotransmitter as well as a source of energy. Transaminases in brain tissue normally convert leucine to α-ketoglutarate to supply nitrogen to the cerebral glutamate pool (6
). Elevated aKIC — the ketoacid derivative of leucine — reverses the net direction of nitrogen flow and thus depletes the brain of glutamate (6
). Consistent with these mechanisms, reduced cerebral dopamine and glutamate levels have been observed in experimental MSUD animals (8
) and postmortem brain tissue from a child who died of leucine intoxication (10
Supporting the energy inhibition hypothesis, BCKDHA
knockout mouse brain has low pyruvate, ATP, and phosphocreatine, and high α-ketoglutarate, lactate, and alanine (9
). In human MSUD patients, magnetic resonance spectroscopy (MRS) studies demonstrate reversible lactate elevation and N-acetylaspartate (NAA) depletion during acute encephalopathic crises, reflecting transient compromise of cerebral mitochondrial function (11
). Cerebral edema during acute crises consists of both a global vasogenic edema thought to be related to blood-brain barrier compromise and “MSUD edema,” which is thought to be intramyelinic, cytotoxic edema secondary to energetic and osmotic dysregulation (12
). Qualitatively similar but less marked mechanisms may also contribute to chronic symptoms in patients considered metabolically stable.
These factors prompted us to characterize neuropsychiatric outcomes in MSUD patients and to determine how they correlate with clinical course, management variables, indices of cerebral essential amino acid nutrition, treatment strategy, and neurochemistry.