Galactosemia:Identification by Metabolic Liver Biopsy

半乳糖血症：代谢性肝活检鉴定

• 批准号: 6863679
• 负责人: STANTON SEGAL
• 金额: $ 16.6万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6863679
• 关键词: acetaminophen; adult human (21+); carbohydrate metabolism; carbon; children; clinical research; enzyme activity; galactose; galactosemias; gene mutation; genetic disorder; genotype; glucuronides; human subject; liver metabolism; nuclear magnetic resonance spectroscopy; nucleotidyltransferase; oxidation; patient oriented research; stable isotope; uridine diphosphate glucose; urinalysis

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.

描述(由申请人提供)： 半乳糖血症是一种神秘的疾病，由于缺乏半乳糖-1-磷酸尿苷转移酶(GALT)而导致遗传不能代谢半乳糖，半乳糖是牛奶中的主要营养物质。半乳糖限制饮食的治疗应用未能预防认知障碍、言语障碍、神经性共济失调和卵巢衰竭的长期并发症。开发新的治疗策略势在必行。大多数患者，即使是那些被认为有严重突变的患者，也有能力将半乳糖缓慢氧化为二氧化碳，这在很大程度上是他们内源性半乳糖产生的处理方式。如果能够描述所涉及的机制(S)，那么增强这种能力可能是一种新的治疗方法。 这项建议的目的是通过一种新的肝脏尿二磷酸葡萄糖(UDPglu)池的“代谢活组织检查”技术来确定半乳糖血症患者是否有残存的GALT活性来解释他们有限的糖代谢能力以及有多少是由其他已知的替代途径解释的。该方法利用~(13)C核磁共振和~1H核磁共振这两个强大的工具来测量口服2-13C半乳糖后24小时尿中对乙酰氨基酚(Tylenol)葡萄糖醛酸苷的总量和~(13)C浓缩度。在9岁以上的受试者中，对乙酰氨基酚主要以葡萄糖醛酸苷的形式排出(65%)，葡萄糖醛酸苷是半乳糖代谢正常途径的关键中间体UDP。发生这种情况的程度将表明正常途径的残留量。这项研究将在正常受试者和Q188R突变纯合子(占高加索患者的50%)、Q188R复合杂合子、我们已知具有残留活性的非裔美国人的S135L以及基因缺失纯合子无法具有任何残留活性的德裔美国人中进行。对不同遗传类型的残存GALT功能进行分析。