Presented by Holmes Morton, MD
Dr. Morton's talk focused primarily on the effect of the disease on the central nervous system.
To illustrate the progress in the treatment of MSUD, Dr. Morton presented the case of a nine-day-old infant. The baby was referred to the Clinic because of a positive newborn screening test. The results were unfortunately late (as many parents have experienced first hand), and the baby was suffering from symptoms of Classic MSUD. However, within 36 hours of treatment, the baby's branched-chain amino acid levels had decreased significantly, and by 48 hours of treatment, the levels were within normal range. After 72 hours of treatment, the baby was taking formula by mouth, and her neurological exams had begun to normalize. By day five, she was ready to go home.
This was accomplished by metabolic management as opposed to the old method of dialysis. Metabolic management involves reducing the levels of the branched-chain a-keto acids and keeping patients hydrated so that these a-keto acids are removed from the body, thus reducing leucine levels.
Dr. Morton dazzled the audience with success stories that were the result of metabolic management. Of the 37 MSUD newborns that were diagnosed and treated by Dr. Morton at his Clinic in Strasburg, PA over the past eight years, 18 were diagnosed 12 to 24 hours postnatally. (This was possible because the parents had been tested and identified as carriers of the MSUD gene or had other children with MSUD.) With good metabolic management, none of these 18 babies became ill. The average hospital stay for Dr. Morton's patients is now 4 days compared to the months of hospitalization endured by patients and families years ago.
Understanding the systemic [pertaining to the whole body] management of MSUD improves treatment. This involves understanding the management of the many variables that make MSUD so complex. These variables include:
- How to decrease leucine levels?
- How to prevent valine and isoleucine deficiency?
- What mixture of amino acids is needed to support normal protein synthesis at a rate that is optimal for normal growth and development?
- What caloric intake is allowable?
- What is the role of other amino acids in supporting a homeostatic environment?
One of the many challenges faced by Dr. Morton, along with other physicians and researchers, is understanding MSUD's effect on the brain. Knowing the level of leucine is important, but it is just as significant to determine the pattern of amino acid variation in general which leads to the neurological symptoms. To emphasize this principle, the audience was given a quick lesson in neuroanatomy. Dr. Morton analyzed and interpreted MRIs and amino acid profiles from the records of several patients with metabolic disorders who were battling cerebral edema.
While treating these patients battling edema, Dr. Morton and his colleague, Kevin Strauss, made a significant observation: the severe edema was very sensitive to extracellular serum osmolarity and their sodium level was related to the brain edema. Dr. Morton concluded that the increased leucine concentrations block the export of other amino acids which require a sodium-dependent transporter for moving efficiently across the cell membrane. This causes the cells to take up more water and swell.
Understanding the effect of MSUD on the brain involves more than understanding cerebral edema. Doctors and scientists need to look deeper and explore the relationship of leucine, valine, and isoleucine to other amino acids essential for the normal functioning of the nervous system. Therefore, the continued progress in the treatment and management of MSUD relies heavily upon diagnosing these patients as newborns in order to develop a better understanding of the interrelationship of leucine, valine and isoleucine to the remaining essential amino acids.