Amino Acid Disorder Laboratory

Harvey L. Levy, M.D.

Amino Acid Disorder Laboratory

In the inborn errors of amino acid metabolism, mental retardation and other neurologic abnormalities are usually the primary clinical features of the disease. These abnormalities also develop in genotypically normal fetuses as in maternal inborn errors. Therapy which at least partially corrects the amino acid and related metabolite levels prevents or modifies these features. Consequently, there is reason to believe that one or more of the observed biochemical abnormalities produce the disease. However, there is virtually no knowledge of the nature of the link between the biochemical and clinical phenotypes with these inborn errors, even for such a frequently studied disorder as phenylketonuria (PKU).

This lack of knowledge hinders our search for improved therapies that could prevent the chronic complications that develop in even treated patients and for therapies for presently untreatable disorders. Information about the nature of these links would be very important for developing these therapies and for advancing our ability to precisely diagnose the disorders and predict prognosis.

As an initial phase in examining this biochemical-clinical link, we are identifying and measuring relevant metabolites in brain and other tissues from fetus and neonates with untreated inborn errors such as nonketotic hyperglycinemia (NKH) and galactosemia and from fetus of untreated maternal PKU pregnancies. The metabolites we are examining include amino acids, nucleotide sugars, glycolipids and fatty acids. Results so far indicate that in maternal PKU the toxic metabolite is phenylalanine and that organic acid metabolites of phenylalanine are not present in the fetus and probably play no role in fetal disease. Conversely, in maternal homocystinuria, very little homocyst(e)ine crosses the placenta, thus accounting for the much less severe fetal effect from maternal homocystinuria than from maternal PKU. In galactosemic brain, several galactolipids are markedly deficient, probably reflecting insufficient production because of deficient uridine diphosphate galactose.

In collaboration with the laboratory of Dr. Verne Caviness, we are examining brain from fetuses with NKH and from untreated maternal PKU pregnancies by light and electron microscopy and by Golgi preparation. We are linking these studies to the biochemical data as to determine similarities and differences in the brain effect between these two major metabolic disorders and among different biochemical phenotypes in each disorder. Other studies in our laboratory and in collaboration with other laboratories include genotypic characterization with phenotype-genotype correlation of individuals with PKU in New England, molecular genetic application for newborn screening using DNA from cells obtained from buccal swabs, improved prenatal diagnosis of NKH, and identification of new sulfur amino acids in a new sulfur amino acid metabolic disorder associated with mental retardation.