Dr. Morton provided attendees with a history of MSUD treatment in the United States. He reports that 1/2 of the children born with MSUD between 1965 and 1986 died of cerebral edema.. Now, in 2016, hospitalizations have been drastically reduced and outcomes greatly improved. It is important to monitor growth charts for evidence of sustained, normal growth.
The Clinic for Special Children in Lancaster, PA has provided accessible and affordable care to over 2200 patients with 127 diff erent recessive disorders, including 90 Mennonite patients with classical MSUD. One area where there has been great improvement is in our understanding of the eff ects of high levels of branched-chain amino acids (BCAAs) on the brain. Leucine has a strong affinity for the protein (LAT 1) which carries it into the brain, so high levels cause the brain to be flooded. At the same time, the entry of other amino acids becomes blocked, creating an imbalance which affects brain chemistry. One consequence of this is the dystonia (muscle spasms) observed when levels are high.
Patient outcome has also improved due to recognition of the importance of supplementing with valine. Previously, valine deficiency led to impaired head and brain growth. Valine has low affinity for the transporter, therefore brain levels are very low when blood leucine levels are high.
Another advance has been the use of BCAA total parenteral nutrition (TPN), which allows for successful surgery and rapid reduction of leucine levels. Dr. Morton suggests that hospitals keep premeasured and sterilized individual amino acids in storage so this option will always be available as an alternative to ordering liquid TPN, which only has a shelf life of about 1 month. In his opinion, this is much safer than dialysis. When cerebral edema is present he suggests giving mannitol, a sugar with high osmolality that is used with head injuries, as it pulls water out of brain and reduces cerebral edema. Lasix (a diuretic) and sodium chloride should also be given to remove extra fl uid and prevent hyponatremia. An individual in a metabolic crisis must be made anabolic (building rather than breaking down body tissues) so they can build protein and reduce blood leucine levels.
Dr. Morton’s second talk of the day addressed transplant and other treatment modalities. He works closely with the transplant team at Children’s Hospital of Pittsburgh, where they have conducted 72 MSUD transplants without any fatalities or need for retransplantation. After transplant, patients are immediately able to process normal amounts of protein and maintain normal blood leucine levels. However, neurological problems including anxiety, mood disorders and sleep disturbances remain. Livers from MSUD patients can be safely transplanted into other patients as most of the enzyme to metabolize BCAAs is in muscle and other tissue.
There have been 3 reported cases of transplanted children who developed encephalopathy after an illness accompanied by dehydration. BCAA levels in these children were elevated, but dropped after IV rehydration. Dr. Morton noted that the transplanted liver can metabolize dietary protein adequately but it has a harder time when the body is in a catabolic state such as occurs with infection. This is especially diffi cult with dehydration. It is essential to monitor amino acid levels during infections, even after transplant.
Amino acid imbalances in the brain appear to persist after transplant. Dr. Morton believes that supplementation with specific amino acids will enable the brain to make neurotransmitters and may help with neurological function.
Stem cell transplantation as a possible therapeutic technique has received attention recently. However based on Dr. Morton’s experience this will only modestly increase BCAA tolerance.
Dr. Morton closed by noting that liver transplant is a drastic intervention using a scarce resource. Follow up is intensive, requiring frequent monitoring and multiple medications. Families shouldn’t give up hope for alternate therapies such as gene therapy where progress has been seen.