In MSUD, there is a metabolic block at the second step of the metabolic process. Babies start out OK, but, if untreated, they will begin with hyperactivity, convulsions, coma and eventually death. There is a rapid progression when the BCAA (branched-chain amino acids) levels become elevated. Ten to fifteen days may be too late to correct any mental problems that occur from the elevated levels.
MSUD is difficult to treat because there are three amino acids to keep balanced instead of just one as in PKU. In the early years, the doctors mixed the child's formula using the required BCAA. At first methionine was also restricted in the diet.
The first child treated was born to a California family in June '59. (A sibling died earlier from MSUD.) It was first thought she had colic but they noticed the sweet odor on the 11th day. She was taken to New York where they confirmed the diagnosis. When the child was around 22 months, blood testing procedures had improved enough to determine a difference between methionine and alloisoleucine. So methionine was added back to the diet. She stayed at the hospital under the care of Dr. Snyderman for four years. She got sick every time they took her home and was not growing well. She was 4¸ years old before she passed the third percentile.
This child moved to OH in '72 and became Dr. Berry's patient. In '77 she joined a group home for women. At 18, her IQ was 64, and she had the social skills of a 12 year old. She eventually got a job at a fast food restaurant. When she started gaining weight, it was suspected that she was cheating on her diet. At 19 years an EEG showed a generalized convulsive disorder. In 1990, she was admitted to a mental institute for confusion. She was placed on her diet and improved. As far as it is known, she still may be cheating, but is doing well. It is important to train physicians to deal with adults with MSUD.
Another child, born in Chicago in 1976, eventually became Dr. Berry's patient. She was hospitalized at one week of age. Although lethargic and not eating, she showed no elevated BCAA levels. She was later released with a diagnosis of a mental episode. In the hospital, she had been on a protein-free IV, so her metabolic condition stabilized. She was hospitalized again at four months of age with projectile vomiting. A nurse noticed the sweet odor leading to a correct diagnosis and treatment for MSUD.
(At this time Scientific Hospital Supplies in England was making MSUD Aid. It was difficult to import as customs raised the fees from 5 to 25%. They said it was a petroleum product.)
This second girl and her family moved to Dayton, OH. A pediatrician cared for her at first and then turned her over to the clinic. In 1978 she became Dr. Berry's responsibility. She had had poor growth and many hospitalizations.
Dr. Berry noted leucine plasma levels were reduced and growth improved when valine was added to the diet. She made a DNPH kit for the mother with the following instructions:
- A trace precipitate within 60 sec. and negative ketones = no treatment required.
- A slight precipitate and negative ketones = watch the patient.
- A moderate precipitate within 30 sec. and positive or negative ketones = increase fluids, decrease BCAA.
- A strong precipitate within 10 sec. and positive ketones = eliminate BCAA from diet; repeat test every 12 hours.
They did a series of studies to see why she had so many hospitalizations. It was determined to be very important to monitor all three amino acids. On a fast, BCAA levels started rising after six days. The lowest level was an hour after each meal and the highest was after an overnight fast. The following guidelines for plasma concentrations were used for treating the patient.
- Leucine: 20 mg/kg or 180-70 micromols/l
- Isoleucine: 12 mg/kg or 70-280 micromols/l
- Valine: 14 mg/kg or 200-800 micromols/l
The girl now has isoleucine and valine added to her formula to keep her levels stable. So far, there have been no more acidotic episodes.
Questions from the audience:
Q. Originally, a girl had her diet supplemented with isoleucine. Now she is 17 and there are no problems with low isoleucine. Why?
A. Dr. Berry feels that puberty may affect MSUD people to the point of improving the tolerance. However, another mother in the audience said her daughter's tolerance is worse since she began puberty.
Q. What would a low leucine level be?
A. 150 to 200 micromols/liter of leucine.
Q. What causes hypoglycemic conditions?
A. High leucine levels seem to affect this condition, but more work is needed before it is fully understood. We need studies to see the relationship between amino acids and insulin.