MSUD Newsletter

Articles selected from Vol. 20, No. 1, Spring/Summer 2002

SUMMARY OF PAPER ON DIAGNOSIS

AND TREATMENT OF MAPLE SYRUP DISEASE*

Dr. Holmes Morton and Dr. Kevin Strauss

* Dr. Morton prefers to call MSUD maple syrup disease.

  This article and the Abstract which follows, “Diagnosis and Treatment of Maple Syrup Disease: A Study of 36 persons” use this term.

Our paper summarizes experiences at the Clinic for Special Children caring for 36 neonates with classical maple syrup disease over an 11 year period. We describe an approach to care that includes diagnosis and management of the at-risk and ill neonate, general pediatric care during common intercurrent illnesses, chronic nutritional care, and in-hospital management of severe metabolic intoxication and brain edema. The effects of maple syrup disease upon the growth, development, and health of the patient are related to many interacting variables which are listed in Table 4—Determinants of Outcome in Patients With Maple Syrup Disease. (See end of article) The medical approach to management of this biochemical disorder must consider such variables throughout the lifetime of the patient. Prevention of malnutrition and intoxication of the brain is obviously just as important for the teenager and adult as for the infant and child.

The management of the disorder during intercurrent illnesses is particularly problematic for parents and physicians. Few follow-up programs have recognized the need to routinely monitor amino acids levels and change management protocols during common illnesses. Our experience clearly shows that episodes of metabolic intoxication that require hospitalization resulted from the stress of intercurrent infections. Equally important, minor illnesses commonly cause increases in blood leucine concentrations and imbalances among the other essential neutral amino acids that compete with leucine for entry into the brain. Such imbalances persist for long periods of time if adjustments in therapy are not made to correct these abnormalities. Chronic deficiencies of valine and tyrosine are particularly common problems in patients with maple syrup disease.

Brain edema remains the most dangerous problem caused by maple syrup disease. It appears to us that there are three phases of brain edema in an ill patient with maple syrup disease. First, there is focal water accumulation in deep gray matter, which is readily seen by brain MRI, and dysfunction of these deep brain ganglia correlates with neurological findings and changes in behavior. Second, diffuse swelling of the brain develops and is seen clinically as somnolence, stupor or coma. This phase of general brain swelling is not well seen by MRI, as is true for early diffuse edema in patients with diabetic coma, hyperammonemia, and hypernatremic dehydration. Third, as the brain volume increases to more than 5-7% of its initial volume, the brain is pressed against the base of the skull, blood flow is interrupted in specific arteries causing focal ischemic strokes, then rapid swelling due to injury and diffuse ischemia, venous congestion, generalized loss of blood flow and brain death.

We have known for several years that brain edema worsens rapidly in association with rapid decreases in serum sodium concentration and osmolarity. Since the submission of this manuscript we have learned that these decreases in serum osmolarity and generalized brain swelling itself may be the result of high levels of a brain hormone called vasopressin.

Two effects of this brain hormone are familiar to all of us—thirst and a concentrated urine. Vasopressin is a hormone that normally protects against dehydration and shock. Vasopressin not only allows the kidneys to hold onto water, it also normally prevents excessive shrinkage of the brain by stimulating the uptake of sodium and water by a diffuse network of cells called astrocytes. Decreases in blood pressure, vomiting, dehydration, high serum sodium, glucose, or urea concentrations (all of which cause increases in serum osmolarity) provoke release of vasopressin by the brain. In the setting of increased blood and brain leucine, hyperosmolar dehydration and the associated prolonged increases in vasopressin become risk factors for the excessive and abnormal uptake of sodium and water by the brain and the development of critical brain edema. Patients at highest risk for brain edema are those who present with advanced signs of leucine intoxication including recurrent vomiting in the setting of dehydration, high serum osmolarity, and who have intense thirst caused by high vasopressin levels. Studies are underway at the Clinic and Lancaster General Hospital using neuro-imaging techniques and endocrinologic monitoring to better understand how to manage such patients to prevent progression to critical edema. We expect such studies will help explain and prevent acute brain swelling associated with maple syrup disease and several different biochemical disorders.

DIAGNOSIS AND TREATMENT OF MAPLE SYRUP DISEASE:

A STUDY OF 36 PATIENTS

D. Holmes Morton, MD; Kevin A. Strauss, MD; Donna L. Robinson, CRNP;

Erik G. Puffenberger, PhD; and Richard I. Kelly, MD, PhD

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 E1α subunit of the branched-chain α-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

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 , Pennsylvania– 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

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