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At Symposium '94 in Columbia, Missouri, Julie Grasela, R.D. used a Q-tip to take samples of cheek cells from volunteers. 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. This report was submitted September 30, 1997 for our MSUD Newsletter. 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). Dr. Phillips is an Assistant Professor, with a Ph.D. in Biochemistry, and a Clinical Molecular Geneticist. Dr. Hillman, who is familiar to many of the MSUD families, is a Professor, Physician, and Metabolic Geneticist. Drs. Hillman and Phillips have put together a research team whose current programs and research studies include:

  1. 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 a-keto acid dehydrogenase (BCKAD) complex which catalyzes the oxidative decarboxylation of the a-keto acids derived from leucine, isoleucine and valine. Clinically the effects are due to the inability to breakdown protein, specifically certain amino acids (isoleucine, leucine, and valine). 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. Infants, whose treatment is begun late, are at risk of neurological damage and mental retardation. 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. In Old Order Mennonite communities of Pennsylvania, the reported incidence of MSUD is 1:176. In Missouri the incidence of MSUD in the Mennonite communities may even be higher, 1:80. Mennonite MSUD patients were found to be homozygous for a T to A transition resulting in a Tyr to Asn change (Y393N) in the E1a subunit of the decarboxylase of BCKAD. This means that both copies of the E1a 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. Phillips' laboratory developed a noninvasive, quick and accurate DNA test. The Y393N alteration can be easily detected using DNA isolated from the loose cells that line the inside of the mouth. Mennonites from several communities have utilized this carrier testing. 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. 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. Four Mennonite families have already benefitted from this newborn screening.
  2. To clearly define the specific alterations in the E1a genes which result in maple syrup urine disease.
    In addition to testing all the Mennonite individuals who requested testing, we have also examined non-Mennonite MSUD patients who wished to be tested. 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 E1a genes. Two non-Mennonite patients were homozygous for the Y393N alteration (both E1a genes had theY393N alteration, similar to Mennonite MSUD patients). Six patients were compound heterozygotes for the Y393N alteration. Since MSUD is an autosomal recessive disorder (requiring both E1a genes, one from mom and one from dad, to be defective), these six patients have the Y393N alteration in one of their E1a genes, and a different alteration on their other E1a allele.

    Determining the other alterations which result in nonfunctional E1a genes is one of Drs. Phillips and Hillman's objectives. Their hope is that knowledge about the alterations which lead to nonfunctional E1a will provide the opportunity to better understand the important structural/functional domains in E1and may lead to better or alternative treatments. 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. To determine the genetic origin of the Y393N alteration (common to Mennonite MSUD patients) in the non- Mennonite MSUD patients. Do these patients have Mennonite ancestors or is this region of the E1a gene susceptible to becoming defective?
    All the Mennonite MSUD patients tested were found to be homozygous for the Y393N alteration in the E1a subunit of the decarboxylase of BCKAD. It is believed that all of the Mennonite MSUD patients inherited their Y393N alterations from a common Mennonite ancestor. 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 E1a gene is more prone to error or change. 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 staff 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, Missouri 65212
Tel: (573) 882-5122 Fax: (573) 884-4597
email: This email address is being protected from spambots. You need JavaScript enabled to view it.

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The MSUD Family Support Group is currently funding several research projects and we are proactively looking for researchers interested in developing new treatments or finding a cure for MSUD. Significant funding is necessary if we are to accomplish this goal.
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