Classical maple syrup urine disease and brain development: Principles of management and formula design

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Abstract

Branched-chain ketoacid dehydrogenase deficiency results in complex and volatile metabolic derangements that threaten brain development. Treatment for classical maple syrup urine disease (MSUD) should address this underlying physiology while also protecting children from nutrient deficiencies. Based on a 20-year experience managing 79 patients, we designed a study formula to (1) optimize transport of seven amino acids (Tyr, Trp, His, Met, Thr, Gln, Phe) that compete with branched-chain amino acids (BCAAs) for entry into the brain via a common transporter (LAT1), (2) compensate for episodic depletions of glutamine, glutamate, and alanine caused by reverse transamination, and (3) correct deficiencies of omega-3 essential fatty acids, zinc, and selenium widespread among MSUD patients. The formula was enriched with LAT1 amino acid substrates, glutamine, alanine, zinc, selenium, and alpha-linolenic acid (18:3n  3). Fifteen Old Order Mennonite children were started on study formula between birth and 34 months of age and seen at least monthly in the office. Amino acid levels were checked once weekly and more often during illnesses. All children grew and developed normally over a period of 14–33 months. Energy demand, leucine tolerance, and protein accretion were tightly linked during periods of normal growth. Rapid shifts to net protein degradation occurred during illnesses. At baseline, most LAT1 substrates varied inversely with plasma leucine, and their calculated rates of brain uptake were 20–68% below normal. Treatment with study formula increased plasma concentrations of LAT1 substrates and normalized their calculated uptakes into the nervous system. Red cell membrane omega-3 polyunsaturated fatty acids and serum zinc and selenium levels increased on study formula. However, selenium and docosahexaenoic acid (22:6n  3) levels remained below normal. During the study period, hospitalizations decreased from 0.35 to 0.14 per patient per year. There were 28 hospitalizations managed with MSUD hyperalimentation solution; 86% were precipitated by common infections, especially vomiting and gastroenteritis. The large majority of catabolic illnesses were managed successfully at home using ‘sick-day’ formula and frequent amino acid monitoring. We conclude that the study formula is safe and effective for the treatment of classical MSUD. In principle, dietary enrichment protects the brain against deficiency of amino acids used for protein accretion, neurotransmitter synthesis, and methyl group transfer. Although the pathophysiology of MSUD can be addressed through rational formula design, this does not replace the need for vigilant clinical monitoring, frequent measurement of the complete amino acid profile, and ongoing dietary adjustments that match nutritional intake to the metabolic demands of growth and illness.

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

References (78)

  • K.A. Strauss et al.

    Prevention of brain disease from severe 5,10-methylenetetrahydrofolate reductase deficiency

    Mol. Genet. Metab.

    (2007)
  • D.M. Killian et al.

    Predominant functional activity of the large, neutral amino acid transporter (LAT1) isoform at the cerebrovasculature

    Neurosci. Lett.

    (2001)
  • M.A. Flynn et al.

    Estimation of body water compartments of preschool children. I. Normal children

    Am. J. Clin. Nutr.

    (1967)
  • V.R. Young

    McCollum award lecture. Kinetics of human amino acid metabolism: nutritional implications and some lessons

    Am. J. Clin. Nutr.

    (1987)
  • J.J. Riviello et al.

    Cerebral edema causing death in children with maple syrup urine disease

    J. Pediatr.

    (1991)
  • G. Huether et al.

    Amino acid depletion in the blood and brain tissue of hyperphenylalaninemic rats is abolished by the administration of additional lysine: a contribution to the understanding of the metabolic defects in phenylketonuria

    Biochem. Med.

    (1985)
  • S.N. Hutchison et al.

    The effect of valine deficiency on neutral amino acid patterns in plasma and brain of the rat

    J. Nutr.

    (1983)
  • J.D. Fernstrom

    Branched-chain amino acids and brain function

    J. Nutr.

    (2005)
  • A.R. Del Angel-Meza et al.

    A tryptophan-deficient corn-based diet induces plastic responses in cerebellar cortex cells of rat offspring

    Int. J. Dev. Neurosci.

    (2001)
  • M.E. Cordero et al.

    Dendritic development in neocortex of infants with early postnatal life undernutrition

    Pediatr. Neurol.

    (1993)
  • S. Diaz-Cintra et al.

    The effects of protein deprivation on the nucleus raphe dorsalis: a morphometric Golgi study in rats of three age groups

    Brain Res.

    (1981)
  • O. Resnick et al.

    Developmental protein malnutrition: influences on the central nervous system of the rat

    Neurosci. Biobehav. Rev.

    (1979)
  • C.D. West et al.

    The effect of a low protein diet on the anatomical development of the rat brain

    Brain Res.

    (1976)
  • M.L. Couce Pico et al.

    Advances in the diagnosis and treatment of maple syrup urine disease: experience in Galicia (Spain)

    An. Pediatr. (Barc.)

    (2007)
  • K.A. Strauss et al.

    Branched-chain ketoacyl dehydrogenase deficiency: maple syrup disease

    Curr. Treat. Options Neurol.

    (2003)
  • D.H. Morton et al.

    Pediatric medicine and the genetic disorders of the Amish and Mennonite people of Pennsylvania

    Am. J. Med. Genet. C Semin. Med. Genet.

    (2003)
  • K.A. Strauss et al.

    Maple Syrup Urine Disease

    (2006)
  • Q.R. Smith et al.

    Blood–brain barrier amino acid transport

  • Q.R. Smith et al.

    Kinetics of amino acid transport at the blood–brain barrier studied using an in situ brain perfusion technique

    Ann. NY Acad. Sci.

    (1986)
  • M. Yudkoff et al.

    Astrocyte leucine metabolism: significance of branched-chain amino acid transamination

    J. Neurochem.

    (1996)
  • M. Yudkoff et al.

    Inhibition of astrocyte glutamine production by alpha-ketoisocaproic acid

    J. Neurochem.

    (1994)
  • P.R. Dodd et al.

    Glutamate and gamma-aminobutyric acid neurotransmitter systems in the acute phase of maple syrup urine disease and citrullinemia encephalopathies in newborn calves

    J. Neurochem.

    (1992)
  • W.J. Zinnanti et al.

    Dual mechanism of brain injury and novel treatment strategy in maple syrup urine disease

    Brain

    (2009)
  • A.L. Prensky et al.

    Brain lipids, proteolipids, and free amino acids in maple syrup urine disease

    J. Neurochem.

    (1966)
  • J. Bryan et al.

    Nutrients for cognitive development in school-aged children

    Nutr. Rev.

    (2004)
  • A.J. Richardson et al.

    The Oxford-Durham study: a randomized, controlled trial of dietary supplementation with fatty acids in children with developmental coordination disorder

    Pediatrics

    (2005)
  • G.S. Young et al.

    Blood phospholipid fatty acid analysis of adults with and without attention deficit/hyperactivity disorder

    Lipids

    (2004)
  • M. Singh

    Essential fatty acids, DHA and human brain Indian

    J. Pediatr.

    (2005)
  • N. Sinn

    Nutritional and dietary influences on attention deficit hyperactivity disorder

    Nutr. Rev.

    (2008)
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