Author's note: The 1990s were proclaimed by the President as the Decade of the Brain. The names of some, certainly not all, of the scientists who made significant contributions to the understanding of this unique metabolic disorder, I have indicated with parentheses. I believe this special decade is a symbol of the enormous benefit of Newborn Screening in recognizing rare metabolic disorders in children before clinical illnesses occurred that often brought them to medical attention. Unfortunately, prevention of brain damage (the cause of mental retardation, cerebral palsy, and epilepsy) has not achieved the recognition it deserves even in this very special decade. My award for this decade acknowledges all these little boys and girls, and their families, who permitted physicians to try to save their lives and "brains" with the limited scientific knowledge we had available.
In 1966, nearly 30 years ago, a two week old infant was transferred to the University of Michigan Hospital with suspected "meningitis." Bacterial meningitis, a central nervous system (CNS) infection, was always the first consideration in a suddenly sick infant. The little baby boy was very sick and in early stages of coma. At the time, no significance was given to a family history of a prior sibling who died in 1958 of an unknown cause. Infection was quickly eliminated in this child. There was not a peculiar "sweet" odor like maple syrup! However, the addition of 2,4-DNPH to the urine gave a strongly positive reaction. The urine also tested positive to Ferric Chloride (FeCl). Both tests were routine in my laboratory as a screen for possible metabolic disorders.
My research was focused on metabolic disorders, especially PKU. Both tests were positive, but FeCl gave a black-brown color rather than the expected "green" observed in PKU. The positive DNPH was also a "strong positive," giving an opaque yellow reaction.Another special test was then done on blood and urine specimens. My NIH grant provided a remarkable new instrument known as an amino acid analyzer. In 1954, the research of Moore, Spackman and Stein first reported the usefulness of this new method, column chromatography. This method permitted the precise quantitative determination of amino acids in small biologic specimens.
We pursued a thorough search of scientific literature. A paper, published in 1954 in a pediatric journal (Dr. J. Menkes) describing a progressive neurological disorder in a family affecting several children with an unusual substance in the urine, proved to be especially interesting. This disorder was one to be identified as maple syrup urine disease (MSUD). I later learned the author of the report, Doctor John Menkes, joined the training program at the Neurological Institute of Columbia University in New York a short time after I completed my training before returning to Ann Arbor.
In the early 1960s other investigators (Dr. J. Dancis) soon identified MSUD as a specific metabolic disorder due to an enzyme deficiency in the metabolism of a specific group of branched chain amino acids (BCAA) that accumulate in body tissues due to a presumed genetic deficiency of a specific enzyme. There had been some confusion about an unexplained increase in an unrelated amino acid, methionine. By refined chemical analysis of specimens from affected patients, this proved to be another amino acid, alloisoleucine, that is unique to MSUD. (Drs. Norton and S. Snyderman)
Initial attempts to treat MSUD took place in London by Drs. Charles Dent and R. Westall in the early 60s. I had the great pleasure of a sabbatical research study in 1969 with Dr. Dent and colleagues (Dr. D.P. Brenton). Previous "visitors" from around the world in "Charlie's" lab included Drs. C. Scriver and M. Efron. His treatment plan with further refinements of the special formula (Drs. S. Snyderman, D. Lonsdale) was accepted. Removal of the BCAA from milk and foods was impossible, but mixtures of amino acids without the BCAA was successful.
Coincidentally, about the same time, another little baby boy was born at the other end of the country in Oregon in March of 1965 who also became sick in early infancy. When the family moved to Indiana, he came to Ann Arbor in 1967 to continue treatment begun in Oregon. Fortunately, he had been tested for MSUD by a new Guthrie test invented by Robert Guthrie, another science superstar in those early years of interest in metabolic diseases. He proposed Newborn Screening (NBS) for all babies, originally PKU and then MSUD. This began the era of NBS that has now been extended to all the United States and many countries around the world, especially for PKU, MSUD, Congenital Hypothyroidism (CH), and several other rare disorders. Yet in 1993, only 24 states have added MSUD to routine newborn screening panels.
These two babies were my first patients with MSUD. There were curious similarities in their lives and in the lives of the families. Both mothers subsequently had other pregnancies resulting in the birth of girls with MSUD. The mother of one had an amniocentesis in 1969 with cells sent to New York for special studies to determine whether the fetus was affected. Unfortunately the cells died during incubation, preventing the completion of tests to establish the diagnosis. That baby did have MSUD, which was established within hours of birth. Had the cells survived, this would probably have been the first inutero diagnosis of MSUD. Both were diagnosed by biochemical assay of newborn blood specimens in the first few hours of life in my laboratory. This allowed a special BCAA-free diet to be started extremely early in the life of these infant girls. They are now healthy, young adults who continue to use the special diet and monitor blood BCAA.
Back in 1966, the blood tests on this first MSUD baby indicated he had MSUD! We concocted a formula of amino acids, vitamins and minerals a little different from Dr. Selma Snyderman's. It was only several years later commercial producers of infant formulas began to provide such products for MSUD. The special formulas for infant PKU were still in trials at this time. Our clinic began to purchase large quantities of amino acids, formulated to our specifications, which we provided other clinics as well. This kept the costs down for families because this was not established treatment according to health providers. Many state public health departments should be acknowledged for stepping into the breech to assure formulas and services were available. This has been a struggle for all of us interested in treating infants affected with these rare disorders often discovered at birth by NBS. It is remarkable to me that while the cost of special formulas seemed quite great, health insurance providers have gradually acquiesced in the approval of other much more expensive child health costs (i.e., neonatal ICUs, organ transplant, etc.), but only to a limited degree for these remarkably beneficial treatment and cost-effective diets in MSUD and other similar disorders!
Nationally and internationally "science clubs" were formed, devoted to the biology of the new group of metabolic diseases designated Inborn Errors of Metabolism. The Society of Inherited Metabolic Diseases was organized in San Francisco in 1972. The first meeting of the Child Neurology Society was held in Ann Arbor in 1972. Parents of children with all types of neuro-metabolic disorders formed a "parent club" (Association of Neuro-metabolic Disorders) to advocate for their children. Contacts with other scientists around the world in the exchange of information about these then rare disorders helped us all to benefit the patients under our care. Babies and children were increasingly being recognized with MSUD. Parents also were advocates and organized families from around the world (Mr. & Mrs. Brubacher) to assure the provision of information and services for all known MSUD families. Physicians became aware that MSUD is among the many causes of neonatal coma. There are now several MSUD variants also. The knowledge of the enzyme defect, the genetics, and the neurology of this acute devastating disease has gradually been established (Drs. D. Danner, L. Elsas & C. Scriver). During acute bouts of metabolic decompensation with ataxia or coma, Total Parental Nutrition (TPN) is a great advance, avoiding the need for dialysis (Drs. G. Gaull & H. Berry).
In 1966 this first MSUD infant spent 8 months in the clinical research unit. Nutrition was a serious problem, with skin breakdown and failure to thrive apparently related to the malnutrition of a special formula lacking essential ingredients. The health of these first two boys was fragile and the intake of special formula a constant problem [for the one boy]. Intermittent bouts of acute illness intervened and occasionally required hospitalization [for the one boy, the other remained very healthy]. Fortunately, both these children had the devoted parents required for successful long term management. Frequent blood analyses required trips to the hospital for arm vein collections. Unfortunately, both boys died during metabolic crises near the end of the first decade of life.
Now newborn infants with MSUD are generally managed on an outpatient basis. Families simply send in a "Guthrie card" with a few drops of blood for the quantitative analyses of BCAA. Parents check the urine at home using DNPH. In clinical metabolic follow-up, Magnetic Resonance Imaging (MRI) is now available to better understand brain changes related to MSUD management. Recent MRI reports suggest these special dietary treatments do have an effect on brain development.
Dietary management still poses some problems; the composition of essential ingredients is not consistent in all formulas. Exact blood titration of individual amino acids during dietary modifications requires an efficient system of blood collection and analysis. Acute metabolic and neurologic episodes continue to be reported. Occasionally the sudden death of a seemingly healthy infant or child with MSUD occurs without explanation. The addition of thiamine has had variable success in clinical management. The neurological outcome appears to be very good, especially when the diagnosis is established early in life. However, there are still international reports regarding MSUD suggesting families and children have limited access to necessary medical care.
Those early days, even with the limited successes we were able to achieve, were very gratifying. I expect the outstanding, ongoing research in metabolism, neurology and genetics will change the care for these infants and children in the next few years. The prevention of mental retardation and brain damage from metabolic disorders is so much more effective now as a result of many scientific contributors. The devotion and support of parents has been essential to the success achieved to date in caring for children with metabolic disorders. (Thanks, Moms and Dads.)
- Richard J. Allen, M.D., Neurologist, University of Michigan, Ann Arbor, Michigan
A brief history of Maple Syrup Urine Disease (MSUD)