Galactosemia:Identification by Metabolic Liver Biopsy

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Galactosemia, the inherited inability to metabolize galactose, a major nutrient in milk, due to deficient galactose-1-phosphate uridyltransferase (GALT), is an enigmatic disorder. The therapeutic use of galactoserestricted diets has failed to prevent long-term complications of cognitive impairment, speech disorders, neurologic ataxias and ovarian failure. The development of new therapeutic strategies is an imperative. Most patients, even those considered to have a severe mutation, have an ability to slowly oxidize galactose to CO2 which accounts in large part for disposition of their endogenous galactose production. Augmenting that ability may be a new therpeutic approach if the mechanism(s) involved can be delineated. The aim of this proposal is to determine, by a new technique of "metabolic biopsy" of liver uridinedisphospho glucose (UDPglu) pool, if galactosemic patients have residual GALT activity to explain their limited ability to metabolize the sugar and how much is accounted for by other known alternate pathways. The method involves the powerful tool of 13C NMR and 1H NMR to measure the 13C enrichment and total quantity of urinary acetaminophen (Tylenol) glucuronide over 24 hr following oral bolus administration of 2-13C galactose with concomittant administration of acetaminophen. Acetaminophen is largely excreted (65%) in subjects over age 9 yr as the glucuronide, which is derived from UDPglu, the key intermediate in the normal pathway of galactose metabolism. The extent to which this happens will indicate how much of the normal pathway remains. The study will be performed in normal subjects and galactosemics homozygous for the Q188R mutation which accounts for 50% of Caucasian patients, Q188R compound heterozygotes, S135L in African Americans who we know to have residual activity and Ashkenazi with homozygous gene deletions who cannot have any residual activity. An analysis will be made of residual GALT function in relation to various genetic types.