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.

Autism in patients with propionic acidemia

“…Abnormal BCAA transport has been suggested to lead to abnormal psychological development in other disorders such as Maple Syrup Urine Disease [8]. Some of the observed changes in BCAA ratios might be a consequence of the use of amino acid based metabolic formulas that are free of the amino acids, valine, methionine, isoleucine and threonine in PA patients.…”

“…This has been also suggested in several publications evaluating the possible correlation between gastrointestinal propionic acid production and autism [18]. Abnormal branch chained amino acid ratios have also been correlated with poor neuropsychologic outcome [8]. With the increasing reported frequency of ASD in the pediatric population one cannot rule out a possible coincidence of the diagnosis of ASD in patients with propionic acidemia [19].…”

“…Several inborn errors of metabolism have been described as increasing a patient's risk for ASD, including lysosomal storage diseases, disorders of the creatine synthesis, disorders of purine and pyrimidine metabolism or dysfunction of the urea cycle, but autistic features are not frequently reported in organic acidemias [5,8,9,10,11]. With the growing frequency of patients being diagnosed with ASD, sometimes it is difficult exclude a coincidental diagnosis of autism in certain metabolic conditions from comorbidity, especially in case of intellectual disability.…”

Branched Chain Amino Acids and Maple Syrup Urine Disease

“…The risks of surgery and immune suppression were not found to be different from those for other pediatric transplant patients and this was considered a potentially cost-effective alternative to lifelong dietary therapy and the risks of recurrent metabolic decompensation. However, recent data shows psychiatric morbidity remains signifi cant in MSUD patients who have undergone liver transplant [ 56 ].…”

“…Mental health outcomes in patients with classic MSUD have been studied by Muelly et al [ 56 ]. They reported on a cohort of 37 patients, aged 5-35 years, with the majority of subjects Old Order Mennonite and homozygous for the BCKDHA c.1312T > A mutation.…”