Article published in Pediatrics, June 4, 2002 issue

Abstract

Goal: To evaluate an approach to the diagnosis and treatment of maple syrup disease (MSD).

Methods: Family histories and molecular testing for the Y393N mutation of the E1a subunit of the branched-chain a-ketoacid dehydrogenase allow us to identify infants who were at high risk for MSD. Amino acid concentrations were measured in blood specimens from these at-risk infants between 12 and 24 hours of age. An additional 18 infants with MSD were diagnosed between 4 and 16 days of age because of metabolic illness.

A treatment protocol for MSD was designed to 1) inhibit endogenous protein catabolism, 2) sustain protein synthesis, 3) prevent deficiencies of essential amino acids, and 4) maintain normal serum osmolarity. Our protocol emphasizes the enhancement of protein anabolism and dietary correction of imbalances in plasma amino acids rather than removal of leucine by dialysis or hemofiltration. During acute illnesses, the rate of decrease of the plasma leucine level was monitored as an index of net protein synthesis or degradation. The treatment protocol for acute illnesses includes the use of mannitol, furosemide, and hypertonic saline to maintain or reestablish normal serum sodium and extracellular osmolarity and thereby prevent or reverse lifethreatening cerebral edema. Similar principles were followed for both sick and well outpatient management, especially during the first year, when careful matching of branched-chain amino acid intake with rapidly changing growth rates was necessary. Branched-chain ketoacid excretion was monitored frequently at home and branched-chain amino acid levels were measured within the time of a routine clinic visit, allowing immediate diagnosis and treatment of metabolic derangements.

Results:

  1. Eighteen neonates with MSD were identified in the high risk group (n=39) between 12 and 24 hours of age using amino acid analysis of plasma or whole blood collected on filter paper. The molar ratio of leucine to alanine in plasma ranged from 1.3 to 12.4, compared to a control range of 0.12 to 0.53. None of the infants identified before three days of age and managed by our treatment protocol became ill during the neonatal period, and 16 of the 18 were managed without hospitalization.
  2. Using our treatment protocol, 18 additional infants who were biochemically intoxicated at the time of diagnosis recovered rapidly. In all infants, plasma leucine levels decreased to less than 400 µmol/l between 2 to 4 days after diagnosis. Rates of decrease of the plasma leucine level using a combination of enteral and parenteral nutrition were consistently higher than those reported for dialysis or hemoperfusion. Prevention of acute isoleucine, valine, and other plasma amino acid deficiencies by appropriate supplements allowed a sustained decrease of plasma leucine levels to the therapeutic range of 100 to 300 µmol/l, at which point dietary leucine was introduced.
  3. Follow-up of the 36 infants over more than 219 patient years showed that, although common infections frequently cause loss of metabolic control, the overall rate of hospitalization after the neonatal period was only 0.56 days per patient per year of follow- up, and developmental outcomes were uniformly good. Four patients developed life-threatening cerebral edema as a consequence of metabolic intoxication induced by infection, but all recovered. These four patients each showed evidence that acutely decreased serum sodium concentration and decreased serum osmolarity were associated with rapid progression of cerebral edema during their acute illnesses.

Conclusions: Classical MSD can be managed to allow a benign neonatal course, normal growth and development, and low hospitalization rates. However, neurological function may deteriorate rapidly at any age because of metabolic intoxication provoked by common infections and injuries. Effective management of the complex pathophysiology of this biochemical disorder requires integrated management of general medical care and nutrition, as well as control of several variables that influence endogenous protein anabolism and catabolism, plasma amino acid concentrations, and serum osmolarity.

This paper is dedicated to children with maple syrup disease and their parents - from your suffering we must learn, and to Halvor Christensen, Ph.D. who in 1949 first observed that high leucine concentrations disturbed the rate of uptake and export of amino acids by tissues. - hm

Table 4. Determinants of Outcome in Patients with Maple Syrup Disease

Neonatal

  • Time required to reduce plasma and tissue leucine levels to normal
  • Prevention of hyponatremia and vascular compression by critical cerebral edema
  • Prevention of prolonged, severe brain essential amino acid deficiency
  • Age at diagnosis
  • Degree of illness at diagnosis

Dietary control when well

  • Methods for home monitoring of metabolic control
  • Adjustments for changes in leucine tolerance as a function of growth velocity
  • Prevention of systemic and brain essential amino acid deficiency
  • Prevention of nutritional deficiencies caused by dependence upon artificial foods

Control of catabolism during intercurrent illnesses or stress

  • Methods for local or home monitoring of metabolic status
  • Effective sick-day management during common infections and after immunizations
  • Timely treatment of common infections
  • Prevention of exercise-induced metabolic decompensation
  • Control of metabolic decompensation caused by cold, heat, or psychological stresses
  • Prevention of central nervous system water intoxication

Acute medical care

  • Access to metabolically-informed medical care during minor illnesses
  • Effective care in hospital during acute illnesses and after injuries or surgery
  • Inhibition of protein catabolism and support of protein synthesis to lower plasma leucine
  • Prevention of peripheral and brain essential amino acid deficiencies
  • Control of uncommon infections: immune dysfunction, central line infections
  • Prevention or effective management of pancreatitis
  • Prevention of water and sodium derangements and regional brain edema
  • Prevention of vascular injuries caused by critical cerebral edema

The complete article, "Diagnosis and Treatment of Maple Syrup Disease: A Study of 36 Patients" as printed in Pediatrics is 10 pages describing the treatment of classic MSUD. The article as published can be viewed on Pediatrics' web site: www.pediatrics.org

Dr. Holmes Morton, Dr. Kevin Strauss, Donna Robinson and Dr. Erik Puffenberger, authors of the above article, are from the Clinic For Special Children, Strasburg, Pennsylvania. See following article on The Clinic for Special Children.


Editor's Note:

Dr. Morton prefers to leave the word "urine" out of MSUD. He calls the disorder "maple syrup disease." The name "maple syrup urine disease" has been used since the disorder was identified in the 1950s. MSUD calls attention to the odor in the urine which is so often a factor in diagnosing the disorder. To avoid confusion this Newsletter will continue to use MSUD. - Jb

The Clinic For Special Children

This unique non-profit Clinic was founded in 1989. Dr. and Mrs. Morton had strong community support in their efforts to provide affordable healthcare for this large community of Amish and Mennonites in Lancaster County, Pennsylvania. Most of these conservative church groups do not carry insurance nor do they use government programs. The Amish families have a high incidence of glutaric aciduria (GA1) and Mennonite families have a high incidence of classic maple syrup urine disease (named Mennonite Classic because of the one single mutation involved). In 1990 many local families helped "raise" the first building for the Clinic in the traditional Amish "barn-raising" style.

The original objective of the Clinic was to treat children with MSUD and GA1 in the surrounding community. However, the need for a similar approach to care for these and other disorders in other locations has increased the demand for clinic services far beyond the original plans. Expanding in size and services, the Clinic has served families from other areas and treated many disorders. Clinic services now include newborn screening and carrier testing for fifteen genetic disorders. The Clinic is also pursuing genetic research in its modern laboratory.

Thirty to forty percent of the Clinic's yearly operating expense is met by funds from three auctions held annually. These auctions and other contributions support the Clinic so families are not unduly burdened with high medical costs.

The auctions are a feast of the finest in Pennsylvania Dutch crafts, quilts, food, handcrafted furniture, items as big as sheds, and many speciality items - all donated. Delicious home-baked items and food stands draw crowds. The huge auctions usually have three or more auction rings going from eight in the morning until late afternoon. For a delightful time and money well spent, include one of these auctions in your summer travels:

  • Shippensburg Auction, Shippensburg, Pennsylvania
  • Blair County Auction, north of Woodbury, Pennsylvania
  • Lancaster County Auction, Leola , Pennsylvaniañ Always held the third Saturday of September

For more information on the Clinic or the auctions, call 717-687-9407 or check the Clinic's new web site: www.ClinicForSpecialChildren.com

- The Editor