Classical maple syrup urine disease and brain development: Principles of management and formula design
Introduction
Classical maple syrup urine disease (MSUD) is caused by deficiency of branched-chain ketoacid dehydrogenase (BCKDH), a mitochondrial enzyme in the degradation pathway of the branched-chain amino acids (BCAAs; leucine, isoleucine, and valine) and their ketoacid derivatives (BCKAs). Acute elevations of leucine and alpha-ketoisocaproic acid (aKIC) cause metabolic encephalopathy and life-threatening brain edema [1], whereas prolonged imbalances of circulating amino acids may have more subtle and lasting effects on brain structure and function [2], [3], [4].
Cerebral amino acid deprivation appears central to the pathophysiology of MSUD. We began to explore this idea in the 1990s, when we encountered equations that describe competitive blood-to-brain transport among 10 amino acids: leucine, isoleucine, valine, phenylalanine, tyrosine, tryptophan, histidine, methionine, threonine, and glutamine [5], [6]. We developed a spreadsheet to estimate blood-to-brain transport from clinical data [5] (Appendix) and found that some MSUD patients may have chronically low cerebral uptake of several amino acids (Fig. 1). Other investigators had shown that aKIC can alter tissue amino acid content by disrupting transamination fluxes [7], [8]. In catabolic muscle, elevated aKIC prevents the normal flow of BCAA nitrogen into glutamine and alanine synthesis [9], [10]. In nervous tissue, where cytosolic and mitochondrial transaminases normally transfer BCAA nitrogen into neurotransmitter pools [7], [11], excess aKIC appears to reverse this flow and deplete tissues of glutamate, glutamine, GABA, and aspartate (Fig. 2) [1], [3], [7], [8], [12], [13], [14], [15].
Between 2003 and 2004, we recognized other nutritional deficiencies that threaten brain development [16], [17], [18], [19], [20], [21]. Most metabolic formulas manufactured at that time had little or no omega-3 polyunsaturated fatty acid (PUFA), and we found that nearly all of our MSUD patients had omega-3 PUFA deficiency [1], [22]. Docosahexaenoic acid (DHA; 22:6n − 3), the PUFA most important for brain function [17], [19], [20], [23], was less than 50% of normal in patient red cell membranes [1]. In 2004, we cared for a 3 year-old MSUD patient who had intractable diarrhea and acrodermatitis due to zinc deficiency. We subsequently identified marginal zinc levels in most of our patients [16], [24], [25]. Like zinc, selenoproteins are enriched in the brain, where they may protect synaptic membranes, myelin, and monoamine transmitters from oxidative damage [25], [26], [27], [28], [29], [30], [31]. Consistent with other reports [27], [32], [33], we found blood selenium levels to be only 40% of normal in our Mennonite MSUD patients.
We hypothesized that a single dietary formulation could be designed to counter the metabolic derangements that cause brain disease while also providing a nutritional safety net against essential lipid and micronutrient deficiencies. We designed a new formula based on four concepts: (1) the composition of amino acids was crafted to optimize the pattern of circulating amino acids that supplies nervous tissue, focusing upon brain uptake of each amino acid, rather than plasma concentration; (2) conditionally essential amino acids such as glutamine and alanine were fortified to buffer against their depletion by high tissue aKIC (Table 1); (3) essential fatty acids, vitamins, minerals, and micronutrients were chosen to support normal development and correct existing deficiencies; (4) based on amino acid monitoring, the dietary prescription was repeatedly adjusted to account for dynamic changes of metabolic homeostasis characteristic of MSUD, especially the frequent catabolic episodes triggered by minor infections [2]. We evaluated the physiologic actions of this new formula over a 33-month trial in 15 Mennonite infants. Our observations provide a robust conceptual framework for the prevention of brain disease in MSUD.
Section snippets
Protocol design
Between September 2005 and June 2008, we studied 15 Old Order Mennonite children with classical MSUD resulting from homozygous c.1312T>A mutations in BCKDHA. Nine children started the new MSUD formula between 1 and 34 months of age (mean age 18 ± 12 months) and six additional children were treated from birth. The average treatment period was 29 ± 7 months (range 14–33 months). The new formula, called Complex Infant (Applied Nutrition Corporation), contained 4.8 kcal/g and had a calorie breakdown of 11%
Growth, development, hospitalizations, and leucine tolerance
Complex Infant was well tolerated and there were no adverse events related to its use. All children grew and developed normally. There were 28 hospitalizations during the study; all but four were due to a common childhood infection (Table 3A). Vomiting was the most common indication for hospitalization (40%). During the study, the frequency and duration of hospitalizations decreased by 68% and 59%, respectively. Interestingly, these rates decreased for all MSUD patients under our care (Table 3B
Discussion
Before 1989, medical care for Mennonite children with MSUD was fragmented and expensive [41]. Nearly half of these children died of brain herniation and many who survived were permanently disabled [2]. The Clinic for Special Children, built in 1989, has since become a medical home to 79 MSUD patients [5], [6], [42]. Early work at the Clinic was focused on integrating metabolic management into general pediatric practice [2], [43]. This led to affordable on-site amino acid testing, the
Conclusions
This study illustrates the complexity of metabolic formula design. It is an iterative process that requires continual reappraisal in light of clinical and experimental data. Our calculations suggest that study formula could be improved by adding more histidine and glutamine (Table 5), as well as adjusting the proportional content of iron, zinc, and selenium (Table 6). The fatty acid data indicate that DHA itself, rather than just its precursors, should be part of the diet (Table 7). Based on
Disclosure statement
The medical food used in this study was manufactured by Applied Nutrition, Incorporated. Applied Nutrition supplied the product to families free of charge for the study period and paid for all laboratory testing used to evaluate product performance and safety. Bridget Wardley is an employee of Applied Nutrition.
Acknowledgments
The authors acknowledge the expertise and cooperation of Lancaster General Hospital’s pediatric nurses, inpatient pharmacists, and radiology technicians, without whom we could not provide dependable local emergency care. Dr. Richard Kelley, M.D., Ph.D., had an important influence in the development of MSUD treatment protocols in the early years of the Clinic. Through advice and personal communications, Drs. Halvor Christensen, Quentin Smith, and Marc Yudkoff made important contributions to the
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These authors contributed equally to this work.