Galactosemia: Identification by Metabolic Liver Biopsy

描述（由申请人提供）： 半乳糖血症是一种遗传性疾病，由于缺乏半乳糖-1-磷酸尿苷酰转移酶（GALT）而导致不能代谢半乳糖（牛奶中的主要营养物质）。半乳糖限制饮食的治疗性使用未能预防认知障碍、言语障碍、神经性共济失调和卵巢功能衰竭的长期并发症。开发新的治疗策略势在必行。大多数患者，即使是那些被认为具有严重突变的患者，也具有将半乳糖缓慢氧化为CO2的能力，这在很大程度上解释了其内源性半乳糖产生的处置。如果能够阐明所涉及的机制，增强这种能力可能是一种新的治疗方法。 本提案的目的是通过一种新的肝尿苷二磷酸葡萄糖（UDPglu）池“代谢活检”技术，确定半乳糖血症患者是否具有残留的GALT活性，以解释其代谢糖的能力有限，以及有多少是由其他已知的替代途径引起的。该方法采用13 C NMR和1H NMR的强大工具，在口服推注2- 13 C半乳糖并伴随给予对乙酰氨基酚后24小时内测定尿中对乙酰氨基酚（泰诺）葡萄糖醛酸苷的13 C富集和总量。对乙酰氨基酚在9岁以上受试者中主要以葡糖苷酸形式排泄（65%），葡糖苷酸来源于半乳糖代谢正常途径的关键中间体UDPglu。这种情况发生的程度将表明有多少正常途径仍然存在。本研究将在正常受试者和Q188 R突变纯合子（占高加索患者的50%）、Q188 R复合杂合子、非裔美国人中的S135 L（我们已知具有残留活性）和具有纯合子基因缺失（不具有任何残留活性）的德系犹太人中进行。将对与各种遗传类型相关的残留GALT功能进行分析。

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.