臺灣博碩士論文加值系統

苯酮尿症(Phenylketonuria簡稱PKU)是我國最常見的遺傳代謝疾病之一，遺傳模式為體染色體隱性遺傳。主要是由於苯丙胺酸(Phenylalanine, Phe)代謝成酪胺酸(Tyrosine, Try)路徑發生了缺陷，導致苯丙胺酸大量堆積而產生了許多有毒的代謝產物。若未及早治療，往往會造成很特殊的臨床症狀及嚴重的智能遲緩。苯酮尿症的平均發生率因不同國家或種族而略有差異，一般在一萬分之一到三萬分之一之間，我國約三萬三千分之一。丙二酮四氫喋呤合成酶(6-Pyruvoyl- tetrahydropterin synthase; PTPS) 的缺陷是藥物型苯酮尿症(BH4 type)中最常見的一種，若未及早治療不但會造成一些苯酮尿症的典型臨床症狀外，還會產生一些神經學方面的臨床症狀。
PTPS 發生缺陷在歐美國家的發生率極低，因此關於此類患者的預後情況的相關報告很少。此類疾病的治療方式是除了給予BH4外並且同時補充神經傳導物質，如:5-hydroxy-tryptophan、Levodopa。關於神經傳導物質的補充目前並沒有一個良好的治療準則，在部分國外的醫學中心建議在使用神經傳導物質藥物治療時，需檢測腦脊髓液(cerebrospinal fluid; CSF)中的神經傳導物質代謝物質來作為用藥的參考依據，但因國情關係此法很難被國內家長所接受。目前用藥的依據是以患者在臨床反應做為用藥依據，我們想知道這樣治療的方式是否恰當，且欲找出影響預後的因子有哪些，希望能藉由此來提供更好的用藥評估及醫療品質。
最近其他醫學中心曾研究發現早期治療的PTPS 缺乏的10位患者，其預後沒有預期上的理想，平均智商76(開始治療年齡平均:43.3±31.7天; 分佈:6-174天)，且認為此類患者於胎兒時期已造成腦部傷害。為了了解我們的患者是否有相同的狀況，我們收集了台北榮總相同情況的12位患者(開始治療年齡平均:19.6±8.7天; 分佈:1-34天)，依照其年齡採用適當的智力量表來作分析比較，得到平均智商為97，兩者之間的比較有顯著的統計學上差異(P<0.05)。而我們的結果也顯示及早治療的病患仍可達到不錯的智能發展。於是我們分析了可能影響智能發展的相關因子及其相關聯性。發現基因型、出生體重百分比及用藥治療時間和智能發展有明顯的關聯性。
另外也針對這群患者的照顧者(父母親)進行遺傳諮詢，內容包括他們對於苯酮尿症遺傳模式與患病風險機率的暸解程度、用藥狀況及照顧情形、患者與照顧者的心理狀態及希望獲得哪些遺傳諮詢或醫療幫助等。

In Taiwan, 6-Pyruvoyl- tetrahydropterin synthase (PTPS) deficiency is the cause of approximately one-third of all cases of hyperphenylalaninemia (HPA). Its prevalence (1/132,000) is considerably higher than that in Caucasian populations (1/1,000,000). This allows us to accumulate more experience in this form of illness within a single medical center. The treatment of PTPS deficiency consists of supplement with BH4 and neurotransmitters, L-DOPA (L-3,4-dihydroxy- phenylalanine) and 5-HTP (5-hydroxytryptophan). Descriptions of the outcomes of patients with PTPS deficiency, particularly over long-term follow-ups on their brain development, remain scarce. The recommend amount of neurotransmitter replacement should be based on the levels of neurotransmitter metabolites in the cerebrospinal fluid (CSF). However, these measurements are generally not feasible due to cultural reasons. Therefore, the administration of each agent was based only on the clinical response and development of adverse effects at our clinics. We have been concerned that replacement of neurotransmitters guided by clinical observations may not be appropriate for these patients, and that the long-term inappropriate treatment may be result in brain damage and gradual neurological dysfunction. In this study, we reviewed the characteristics of 12 PTPS-deficiency patients whose inborn error of metabolism was identified by newborn screening and accepted early treatment. All of these patients have been followed up at our clinics for more than 5 years (ranged 5-20 years). The correlations among treatment, clinical manifestations, biochemical findings, genotypes, and outcomes were analyzed. The average intelligence quotient (IQ) scores of these patients were 97. The genotype, birth body weight percentage and the age at commencement of BH4 and neurotransmitters replacement had a significant correlation with the outcome IQ scores. Our results revealed that the outcome of the early-treated PTPS deficiency patients is as good as that of classical phenylketonuria patients under diet restriction therapy, even though the adiministration of neurotransmitters was based primarily on the observation of clinical responses and adverse effects. In addition, we carried out genetic counseling for their parents and evaluated their knowledge about genetic information and risk assessment of PTPS deficiency、compliance of therapy of these patients.

誌謝----------------------------------------------------------------------------------------- i
中文摘要---------------------------------------------------------------------------------- ii
英文摘要---------------------------------------------------------------------------------- iv
目錄----------------------------------------------------------------------------------------- vi


緒論----------------------------------------------------------------------------------------- 1
研究目的---------------------------------------------------------------------------------- 7
研究方法及工具----------------------------------------------------------------------- 13
結果----------------------------------------------------------------------------------------- 17
討論----------------------------------------------------------------------------------------- 22
參考文獻---------------------------------------------------------------------------------- 34
圖表說明---------------------------------------------------------------------------------- 39
附錄----------------------------------------------------------------------------------------- 45
附錄圖表---------------------------------------------------------------------------------- 57

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