M S U D Newsletter Volume 15 #2

M S U D Newsletter

Articles selected from Vol. 15 No.2, Fall/Winter 1997-98

MSUD AND PREGNANCY

In the December â90 issue of the Newsletter we congratulated Sue Ann McNight for making medical history.Ê She gave birth to a healthy 5 pound, 12 ounce baby girl on November 17, 1990.Ê Sue Ann has classic MSUD.Ê Following is an account of her second pregnancy as reported by her metabolic nutritionist, Sandy van Calcar from the University of Wisconsin Biochemical Genetics Clinic in Madison, Wisconsin.Ê Sue Ann shares her own account of her struggle with Guillain-BarrŽ Syndrome and her pregnancy and delivery of her son in the SHARING section of this issue.

As many of you know, Sue Ann McKnight is one of the oldest individuals with MSUD who has been treated since infancy.Ê She delivered a healthy girl, Amanda, about 6 years ago and the outcome from that pregnancy was published (see references).Ê Amanda is now in kinderarten and is doing great!Ê Sue Ann delivered a baby boy, Blake, in March of this year [1997].Ê Iâd like to share some of the details from this pregnancy.

Sue Ann has a higher tolerance for leucine than many individuals with classic MSUD.Ê Because of this, she counts grams of protein rather than leucine and is allowed 29 grams of whole protein from food and whole milk which she adds to her formula.Ê This amount of protein is equivalent to 2000 mg of leucine per day.Ê When Sue Ann gets ill, she rarely has problems because of her MSUD.Ê Since her last pregnancy, she suffered from metabolic acidosis only once when she developed Guillain‑Barre Syndrome three years ago.Ê (Guillain‑BarrŽ Syndrome is caused by nerve inflammation which results in progressive weakness and paralysis.)

Sue Ann presented to our clinic with her second pregnancy at 5 weeks of gestation.Ê Her leucine level was 191 µmol/l (2.5 mg/dl).Ê To meet her nutrition needs during pregnancy, we increased her protein equivalents from formula by adding MSUD 2 to her usual formula of Ketonex II.Ê She also started a prenatal vitamin and extra calcium.Ê Her leucine prescription was not changed.

During this pregnancy, Sue Annâs weight gain was normal and DNPH remained negative.Ê We followed the same lab monitoring protocol that we developed after her first pregnancy (see Table 1).Ê Her free carnitine in plasma decreased below 20 µmol/l at 8 weeks gestation and so carnitine was started at 20 mg/kg.Ê During both the first and second trimester, her leucine prescription changed little (see Table 2).Ê An increase of only 200 mg leucine in her diet increased plasma leucine above 200 µmol/l (2.6 mg/dl).

Table 1:Ê Suggested Monitoring Protocol for Pregnant Women with MSUD*

Analyte

1st & 2nd Trimester

3rd Trimester

Urine ketones

Daily

DNPH

Weekly in the morning

Daily in the morning

Amino acids (Pl & Ur)

Every 2 weeks

Weekly

Carnitine (Pl & Ur)

Monthly

Every 2weeks

Urine organic acids

Once per trimester

Every 2 weeks

Albumin

Once per trimester

Hemoglobin & Hematocrit

Once per trimester

Weight gain

Every two weeks

Weekly

*Assuming no signs of metabolic decompensation are noted.Ê From reference #2

Table 2: Average Plasma amino acids and dietary intake for second pregnancy

Leucine

Valine

Isoleucine

Average leucine intake

µmol/l

(mg)

1st Trimester

128

143

2000

2nd Trimester

167

206

2000

3rd Trimester

288

303

131

2200

Normal values:

leucine

120 +/‑ 32 µmol/lÊ (1.6 mg/dl)

valine

225 +/‑ 50 µmol/lÊ (2.6 mg/dl)

isoleucine

57 +/‑ 20 µmol/lÊ (1.6 mg/dl)

An ultrasound at 16 weeks of gestation showed that the baby was small but had normal development for his age.Ê We increased her carnitine and protein equivalents from formula to see if this would improve the babyâs growth.Ê Another ultrasound at 23 weeks of gestation again showed a small baby, but normal development and growth rate.Ê Sue Annâs metabolic labs remained within normal range.

Ultrasound at 27 weeks of gestation showed that the baby was falling from the 10 percentile for growth and a nonstress test showed decelerations, or slowed blood flow, for the baby.Ê Sue Ann was admitted at that time for further evaluations.Ê Her metabolic labs were again normal.Ê We increased her whole protein intake and carnitine dose.Ê An additional 280 mg leucine in diet increased her plasma leucine to 417 µmol/l (5.6 mg/dl).

During the two week admission, the baby was monitored daily with nonstress tests and biophysical measurements.Ê These measurements were encouraging until 29¸ weeks of gestation when the tests again showed fetal decelerations with decreased tone and activity.Ê A small pleural effusion and ascites (fluid in lung cavity) were found on ultrasound.Ê Because of these problems, the baby was immediately delivered by C‑section.Ê He weighed 584 grams (1 pound 4.6 oz) and his length was 11¹ inches.Ê Apgar scores were 3 and 7 at 1 and 5 minutes.

The baby initially required mechanical ventilation and had other problems typically associated with prematurity including bronchopulmonary dysplasia, jaundice, anemia and retinopathy.Ê He required a neonatal ICU stay of 83 days.Ê At discharge he weighed 4 pounds and was 16 inches in length.

Fetal growth and Sue Annâs leucine tolerance were much different with this pregnancy than with her first one.Ê During the first pregnancy, her tolerance for leucine was much greater.Ê At the end of the second trimester she was tolerating 3800 mg leucine compared with 2200 mg during the second pregnancy. With the first pregnancy, fetal growth delay was detected much later in pregnancy (32 weeks of gestation) and it was not as severe as with the second baby.Ê When we detected the growth delay with her first pregnancy, we were able to gradually increase her leucine intake without causing elevated plasma leucine levels.Ê By the end of her first pregnancy, she was taking 8600 mg of leucine per day without causing an increase in plasma levels.Ê This was 4600 mg more than her prepregnancy tolerance!

During the first pregnancy, she also needed more carnitine to maintain normal blood levels.Ê Her final carnitine dose was 150 mg/kg for the first pregnancy compared with a dose of 50 mg/kg for the second one.Ê For the first pregnancy, both the increase in protein and carnitine seemed to improve the babyâs growth during the final 6 weeks of pregnancy.Ê With the second pregnancy, the babyâs growth did not improve.

After her second delivery, studies of placenta tissue showed multiple small thrombosed vessels (blood clots) which were consistent with chronic ischemia (deficient blood supply).Ê These findings could explain the babyâs small growth since he likely was not receiving adequate oxygenation or nutrients.Ê The deficient placental blood flow could also explain why Sue Annâs branch chain amino acid tolerance did not increase during the second pregnancy.Ê Since the fetus was not receiving adequate amino acids via the placenta,Ê Sue Annâs plasma leucine levels increased even with small increases in intake.Ê We do not have any idea whether MSUD had a role in the development of poor placental blood flow.Ê It seems unlikely given Sue Annâs excellent metabolic control, although conceivably, there may have been a period of high levels that we did not know about.

Blake is now 8 months old and despite the pregnancy complications, he continues to catch‑up in both growth and development.Ê We are optimistic that he will not have any long term complications from his prematurity.Ê I know that he will have every advantage because of the great care he will receive from his parents, Sue Ann and Loni.

van Calcar S.C., Harding C.O., Davidson S.R., Barness L.A., Wolff J.A.Ê Case reports of successful pregnancy in women with maple syrup urine disease and propionic acidemia.Ê Am J Med Gen 44: 641‑646, 1992.2.

van Calcar S.C., Wolff J.A.Ê Nutrition Support of a pregnant woman with maple syrup urine disease.Ê Metabolic Currents, Ross Labs 6(3): 13‑18, 1993.

÷Sandy van Calcar

RESEARCH AND

CARRIER TESTING FOR MSUD

At Symposium â94 in Columbia, Missouri, Julie Grasela, R.D. used a Q-tip to take samples of cheek cells from volunteers.Ê These samples were used for DNA tests in an effort to see if non-Mennonite persons with MSUD could be carriers of the specific classic type of MSUD found in the Mennonite population.Ê This report was submitted September 30, 1997 for our MSUD Newsletter.Ê It explains the studies being done at the University of Missouri Medical School, Columbia, Missouri.

Drs. Charlotte L. Phillips and Richard E. Hillman of the University of Missouri School of Medicine, Departments of Biochemistry and Child Health have an ongoing research program investigating the genetic basis of maple syrup urine disease (MSUD).Ê Dr. Phillips is an Assistant Professor, with a Ph.D. in Biochemistry, and a Clinical Molecular Geneticist.Ê Dr. Hillman, who is familiar to many of the MSUD families, is a Professor, Physician, and Metabolic Geneticist.Ê Drs. Hillman and Phillips have put together a research team whose current programs and research studies include:

1)Ê Genetic testing for the MSUD alteration common to the Mennonite community; providing carrier detection and newborn screening for Mennonite communities.

For review, MSUD is an autosomal recessive metabolic disorder due to a defect in the branched-chain α-keto acid dehydrogenaseÊ (BCKAD) complex which catalyzes the oxidative decarboxylation of the α-keto acids derived from leucine, isoleucine and valine.Ê Clinically the effects are due to the inability to breakdown protein, specifically certain amino acids (isoleucine, leucine, and valine).Ê Children born with classic MSUD are healthy and appear normal at birth, but within 7 to 10 days they have poor feeding, become lethargic, go into a coma and die if untreated. Treatment is essentially a low protein diet with controlled amounts of isoleucine, leucine, and valine.Ê Infants, whose treatment is begun late, are at risk of neurological damage and mental retardation.Ê It is believed that the earlier infants are identified, the better the prognosis.

The prevalence of MSUD in the general Caucasian population is 1:225,000.Ê In Old Order Mennonite communities of Pennsylvania, the reported incidence of MSUD is 1:176.Ê In Missouri the incidence of MSUD in the Mennonite communities may even be higher, 1:80.Ê Mennonite MSUD patients were found to be homozygous for a T to A transition resulting in a Tyr to Asn change (Y393N) in the E1α subunit of the decarboxylase of BCKAD.Ê This means that both copies of the E1α gene that were inherited, one from mom and one from dad, contain the Y393N alteration and is the reason these patients have MSUD.

In response to the request of two Missouri Mennonite communities for carrier testing, Dr. Phillipsâ laboratory developed a noninvasive, quick and accurate DNA test.Ê The Y393N alteration can be easily detected using DNA isolated from the loose cells that line the inside of the mouth.Ê Mennonites from several communities have utilized this carrier testing.Ê Drs. Phillips and Hillman hope to identify all the families at risk for an infant with MSUD, in order to insure rapid detection and treatment of the newborn. Those families in which both parents are carriers, can now be prepared to have their newborn infants tested immediately after birth.Ê The hope is to identify the MSUD infants (within 36 to 48 hours after birth) and place them on the special diet before they become ill or can suffer any neurological damage.Ê Four Mennonite families have already benefitted from this newborn screening.

2)Ê To clearly define the specific alterations in the E1α genes which result in maple syrup urine disease.Ê

In addition to testing all the Mennonite individuals who requested testing, we have also examined non-Mennonite MSUD patients who wished to be tested.Ê In the non-Mennonite MSUD population (many of which were sampled during the MSUD symposium in June 1996, Ohio), we determined that approximately 25 percent of the non-Mennonite MSUD patients had the Y393N alteration in at least one of their E1α genes.ÊÊ Two non-Mennonite patients were homozygous for the Y393N alteration (both E1α genes had theY393N alteration, similar to Mennonite MSUD patients).Ê Six patients were compound heterozygotes for the Y393N alteration.Ê Since MSUD is an autosomal recessive disorder (requiring both E1α genes, one from mom and one from dad, to be defective), these six patients have the Y393N alteration in one of their E1α genes, and a different alteration on their other E1α allele.

Determining the other alterations which result in nonfunctional E1α genes is one of Drs. Phillips and Hillmanâs objectives.Ê Their hope is that knowledge about the alterations which lead to nonfunctional E1α will provide the opportunity to better understand the important structural/functional domains in E1α and may lead to better or alternative treatments.Ê An additional benefit to the immediate families is the knowledge of their own cause for MSUD and may permit more informed prenatal and postnatal genetic counseling.

3)Ê To determine the genetic origin of the Y393N alteration (common to Mennonite MSUD patients) in the non- Mennonite MSUD patients.Ê Do these patients have Mennonite ancestors or is this region of the E1α gene susceptible to becoming defective?

All the Mennonite MSUD patients tested were found to be homozygous for the Y393N alteration in the E1α subunit of the decarboxylase of BCKAD.Ê It is believed that all of the Mennonite MSUD patients inherited their Y393N alterations from a common Mennonite ancestor.Ê Dr. Phillips is interested in determining if the Y393N alteration in the non-Mennonite MSUD patients is from this same Mennonite ancestor, or is it an alteration that arose independently, because this part of the E1α gene is more prone to error or change.Ê By using DNA markers and examining the DNA near the Y393N alterations, this question should be answerable.

This work would not be possible without the volunteer time and efforts of the clinical and research staffÊ at the University of Missouri School of Medicine and donations from MSUD families to the Medical Genetics Research Fund.

For more information contact:

Charlotte L. Phillips, Ph.D.

Departments of Biochemistry and Child Health

Division of Medical Genetics

University of Missouri Medical School-Columbia

M121 Medical Sciences Bldg.

Columbia, MissouriÊ 65212

Tel: (573) 882-5122Ê Fax: (573) 884-4597

email: Phillipscl@missouri.edu

Family History

Krista Olstad

The Oldstads sent this history in April â97 along with a newspaper clipping of an article describing Kristaâs care and the way it has affected her family.Ê The article included a large color photo of the family÷Todd, Carlene, and their two children, Trevor and Krista.Ê It is encouraging to see the media publicizing MSUD.

We had a daughter, Jessica, who passed away twelve years ago.Ê The doctors had discovered that her diaper smelled sweet÷thatâs how they found out that Jessica had MSUD.Ê But the doctors were unable to figure out what was wrong soon enough to treat her. For this reason our pediatrician, Dr. Bilgi was aware of what to look for when our daughter Krista was born.

Krista Olstad was born at Mercy Hospital in Des Moines, Iowa on January 29, 1996.Ê It was a normal birth÷everything went quickly for us.Ê As soon as Krista was born, they started their testing.Ê The day we were to be discharged, Dr. Bilgi called and said one of Jessicaâs diapers had a sweet odor to it.Ê We put Krista into the ICU at the hospital and started the treatment for MSUD.Ê The following day we got some test results back which indicated MSUD.Ê We transferred Krista to the University of Iowa Hospitals.Ê There Krista was put in the hands of Dr. William Rhead, Judy Miller, and Cheryl Stimsom.Ê

Carlene went with Krista that night.Ê I stayed home to take care of our son, Trevor, and to explain to him what was going on with his sister.Ê Trevor, who is six years old, doesnât have MSUD.Ê He stayed with friends for a few days.Ê We were about two hours away from home.

The next day Carlene and I met with our doctors and others who told us that Krista has MSUD.Ê During the next few days we were told a lot more about the disease.Ê Krista was in intermediate ICU.Ê We both were very nervous the first few days because itâs a very big hospital, and we were hoping that Krista wouldnât get worse.Ê Our doctors were great in keeping us informed about her progress.

Everyone was very helpful the whole time we spent there.Ê The nurses in that ICU let Carlene and me help do things so that we could stay busy.Ê Krista was on an IV and also bottle feeding.Ê At times she didnât want anything to do with her bottle.

They had to put an NG tube in Krista and feed her that way most of the time.Ê Carlene and I were able to help feed her and we were also taught how to change her tube which was sometimes hard to do.Ê Judy Miller showed us how to do this and how to check the ketone level in her urine.Ê We put cotton balls in her diaper and then put the wet cotton in a syringe to squeeze out the urine to collect it for the test.Ê (Great idea!)

Cheryl Stimsom showed us how to mix Kristaâs formula.Ê The first few days at home we had problems with this, but we called Cheryl and Judy about it.Ê They helped us.Ê I had started to mix the formula and did it wrong.Ê Now Carlene mixes it every day.Ê It is better to have one person do the mixing, but I know how in case I have to.

Judy had to teach us how to do heel sticks÷we are using Kristaâs toes now.Ê That blood goes to New York.Ê When we have blood drawn at our hospital, it goes to Utah.Ê It used to go to the University of Iowa.Ê They had to close the lab there which really worried us.Ê They had done our tests right away for us, so we were always getting a quick turn around on results.

Krista was at the University of Iowa hospital for ten days.Ê We were nervous about taking her home.Ê But she has been hospitalized only once in her first year.Ê That was for one week.Ê Krista had a cold and ear infection.Ê Dr. Bilgi had seen her a day before she went into the hospital.Ê We thought the medication she was on hadnât taken effect yet.Ê Krista was sleepy and whining that day.Ê When I checked her ketones that night, her levels were real high.Ê We called Dr. Bilgi right away and he told us to take Krista to the hospital immediately.

She was admitted, started on an IV, and taken off her formula.Ê After a couple of days, she got back on formula.Ê After a few more days, her levels starting coming down.Ê We got real scared when her ketones got that high.Ê We had never had anything but a negative reading on her Keto Stixs.

Krista has been easy to manage with her MSUD.Ê She started walking at about ten months.Ê She is real good in nature÷always happy and loves to play with her toys.Ê Krista also loves to give hugs to people and play with her brother and other kids.

Lots of family and friends helped us out when we were at University of Iowa Hospitals.Ê We see Dr. Rhead, Judy Miller, and Cheryl Stimsom at least once a month at the Childrenâs Clinic at University of Iowa, and see Dr. Bilgi when Krista needs a checkup.Ê All these people have made it easy for Carlene and me to keep Krista healthy.Ê We think the world of them for being so caring.

Update: December 1997

Since we sent the history in April, Krista has been in the hospital twice, the last time being the week before Thanksgiving.Ê Both times she had a flu which sent her ketones up.Ê Her three amino acid levels went up a little, too.Ê So we put her in the local hospital on an IV for her dehydration, but each time it was only for a week.

Krista has been really doing well.Ê Her weight is about 25 pounds and height is about 31 inches.Ê Sometimes she doesnât want to eat certain things, like her peas, green beans and some other vegetables.Ê But Krista loves corn, bananas and popsicles.Ê We got some low protein recipe books, so weâre able to start making more foods for her.Ê Kristaâs formula is a mixture of Ketonex and Isoleucine and a little 2% milk.Ê My wife sometimes makes some of it into a paste which Krista takes along with water and other fluids.

We do checkups at the University of Iowa every couple months now.Ê They say Krista is doing really well.Ê She is doing what every 21 month old is doing.Ê She is learning a few new words every day with the help of her older brother who is eight.

We take Krista to a local lab to have blood drawn every four weeks to test her three amino acid levels.Ê This blood is sent to a lab in Texas.Ê In the weeks between those draws, we draw blood at home using filter paper and send it to New York to check her leucine level.Ê This all helps us regulate Kristaâs Diet.

Krista does well in playing with other children at day care.Ê We have a very good day care.Ê They have had Krista since birth and really watch her.Ê If they sense something is wrong, they call one of us right away.Ê We have a lot of good people that take good care of Krista.

÷Todd Olstad

DIET WISE

Recipes

Scalloped Potato Casserole

Submitted by Ruth Leid

2 T. butter (28 gm)

1 lb. raw potatoes, shredded (448 gm)

2 T. wheat starch or cornstarch

¸ onion, chopped (40 gm)

1 c. water

¸ t. salt

¸ pkg. George Washingtonâs Seasoning (Brown or Golden)

² oz. (1¸ T.) heavy whipping cream (23 gm)

Melt and brown the butter slightly.Ê Add the wheat starch and stir until smooth.Ê Add water slowly, stirring constantly, cooking until thickened.Ê Combine with other ingredients.Ê Bake in a covered casserole at 350¡ for 1 hour.Ê Divide into 6 servings.

Protein

Leucine

Calories

Per recipe:

8.8 gm

546 mg

742

Per serving:

1.5 gm

91 mg

124

Hint: Great for the whole family.Ê Brenda Wenger, who likes to take it along to potluck dinners, sometimes adds other vegetables for variety.Ê (Adjust food values accordingly.)

Waffles

Submitted by Verna Zimmerman

1 medium egg white (29 gm)

3 T. margarine

2 c. Dp Baking Mix

1 c. water

1¸ t. baking powder

2 drops yellow food coloring

2 T. sugar