發(fā)布時間：2018-02-23 07:51

  本文關(guān)鍵詞： 原發(fā)性肉堿缺乏癥 新生兒疾病篩查 串聯(lián)質(zhì)譜 基因 治療 預(yù)后　出處：《浙江大學(xué)》2015年博士論文　論文類型：學(xué)位論文

【摘要】：研究目的： 探討新生兒原發(fā)性肉堿缺乏癥(PCD)的患病率、基因譜及臨床特征,為早期診斷提供依據(jù)。 研究方法： 采用串聯(lián)質(zhì)譜分析技術(shù),對2009年1月至2014年12月在浙江大學(xué)醫(yī)學(xué)院附屬兒童醫(yī)院新生兒疾病篩查中心的新生兒進行疾病篩查,收集所有經(jīng)診治、隨訪的PCD確診病例和致病基因攜帶病例,分別記錄其性別、孕周、出生體重、采血日齡、初篩時血漿游離肉堿(CO)水平、用藥劑量、CO水平恢復(fù)正常所需時間、家族史、臨床表現(xiàn)、相關(guān)體格檢查和實驗室檢查、心電圖及影像學(xué)表現(xiàn)、基因檢測結(jié)果、隨訪時間及預(yù)后,以及母親年齡和血漿CO水平。 研究結(jié)果： 1.6年間共篩查新生兒1,119,198例,發(fā)現(xiàn)PCD確診病例共50例,患病率約1：22,384；其中足月兒48例、早產(chǎn)兒2例；男女比1：1.38,平均孕周38+周,平均出生體重3270g,平均采血日齡3.7天,母親平均年齡28.1歲。致病基因攜帶病例共27例,均為足月兒,男女比例1：1.07,平均孕周39+周,平均出生體重3300g,平均采血日齡3.6天,母親平均年齡28.5歲。 2.確診組檢測基因33例,共檢測到23種、67個突變位點,大多數(shù)集中于外顯子1、4、8。共發(fā)現(xiàn)11種已知致病突變位點,分別為c.1400CG(p.S467C). c.760CT(p.R254X)、c.51CG(p.F17L)、c.865CT(p.R289X)、c.1195C T(p.R399W)、c.338GA(p.C113Y)、c.845GA(p.R282Q)、c.428CT(p.P143L)、 c.1433CT(p.P478L)cc.505CT(p.R169W)、c.652+1GA,和12種新發(fā)突變位點,c.308TG(p.V103G)、c.1505CA(p.T502K)、c.1445AG(p.Y482C). c.538CG(p.Q180E)、c.1427TC(p.L476P)、c.40TA(p.W14R)、c.1362T G(p.Y454X)、C.1252CT(p.Q418X)、c.42GA(p.W14X)、c.498-2AG、 c.507de1G(p.R169RfsX5)、c.252_265dup14(p.I89TfsX46)。其中,最常見的突變位點為c.1400CG(p.S467C),出現(xiàn)頻率約34.3%；其次是c.760CT(p.R254X)(19.4%)和c.51CG(p.F17L)(11.9%)。 3.攜帶組檢測基因6例,母親中共檢測到4種、12個突變位點,包括1種未知突變位點c.497+1GT和3種已知致病突變位點c.1400CG(p.S467C)、c.760CT(p.R254X)及c.51CG(p.F17L);最常見突變位點為c.1400CG(p.S467C),出現(xiàn)頻率75%。6例嬰兒中的4例攜帶c.1400CG(p.S467C)突變,2例分別攜帶c.51CG(p.F17L)、c.760CT(p.R254X)突變；其中c.1400CG(p.S467C)突變?nèi)詾樽畛Ｒ娡蛔兾稽c,出現(xiàn)頻率約66.7%。 4.初次篩查(以下簡稱初篩)時,確診組患兒的平均血漿CO水平為[(7.70±2.70)μmol/L],攜帶組為[(6.43±2.33)μmol/L],均低于正常,但組間無顯著差異(p0.01)。確診組用藥前的血漿CO水平呈下降趨勢,而攜帶組則呈上升趨勢,二者存在顯著差異(p=0.000)�；謴�(fù)時間上,確診組(中位數(shù)32天)顯著長于攜帶組(中位數(shù)26天)(p=0.000)。 5.確診組患兒除8例失訪、2例中斷治療外,均無任何PCD相關(guān)癥狀；16例攜帶組母親有腿酸、易疲勞、低血糖發(fā)作等癥狀。 6.確診組有4例患兒同胞行基因檢測,結(jié)果2例為PCD患者,2例為攜帶者。 7.除失訪者外,確診組平均隨訪時間為19.7個月,遵醫(yī)囑服藥、定期復(fù)查者預(yù)后良好。2例自行停藥患兒1例猝死,1例感染后瑞氏綜合征樣腦病發(fā)作。 8.純合突變病例在初篩血漿CO水平、恢復(fù)時間、臨床表現(xiàn)方面與雜合突變病例不存在顯著差異(p0.01)。 結(jié)論： 1.原發(fā)性肉堿缺乏癥為最常見的脂肪酸代謝異常疾病之一,本省新生兒患病率高于目前文獻(xiàn)報道。 2.大多數(shù)突變集中于外顯子1、4、8,占所有突變的77.6%。其中,c.1400C G(p.S467C)、c.760CT(p.R254X)、c.51CG(p.F17L)突變是新生兒PCD最常見的基因突變位點,約占所有突變的65.6%(依次為34.3%、19.4%、11.9%)。c.1400CG(p.S467C)突變是母親PCD患者的最常見突變位點(75%)。 3.單憑新生兒初篩血漿CO水平無法區(qū)分PCD確診者與攜帶者；但母親血漿CO水平正�；蚵缘陀谡！⒂盟幥把獫{C0呈下降趨勢、用藥后恢復(fù)時間長等因素,均是診斷PCD的有力依據(jù)。 4.早期發(fā)現(xiàn)、規(guī)范治療、長期隨訪者預(yù)后良好；中止治療可誘發(fā)嚴(yán)重臨床事件。 5.未發(fā)現(xiàn)新生兒PCD患者基因型與表現(xiàn)型的相關(guān)性。
[Abstract]:The purpose of the study is:
To explore the prevalence, gene spectrum and clinical characteristics of neonatal primary carnitine deficiency (PCD), and to provide a basis for early diagnosis.
Research methods:
The analysis of tandem mass spectrometry, on January 2009 to December 2014 at the children's Hospital Affiliated to Medical College of Zhejiang University neonatal screening center of neonatal disease screening, collect all confirmed cases of PCD after treatment, and follow-up of pathogenic gene carrying cases were recorded the sex, gestational age, birth weight, blood age, screening of plasma free carnitine (CO) the level of dose, CO levels returned to normal time, family history, clinical manifestation, physical examination and laboratory examination and imaging manifestations, ECG, gene analysis, follow-up and prognosis, and maternal age and the level of plasma CO.
The results of the study:
Between 1.6 and 1119198 neonates were screened and found PCD cases were 50 cases, the prevalence rate of about 1:22384; 48 cases of full-term infants, 2 cases of premature infants; and the ratio of 1:1.38, the average gestational age of 38+ weeks, the average birth weight of 3270g, the average was 3.7 days, with an average age of 28.1 years. The mother of pathogenic gene carrying case a total of 27 cases were full-term infants, male to female ratio was 1:1.07, the average gestational age of 39+ weeks, the average birth weight of 3300g, the average was 3.6 days, the mother with an average age of 28.5.
2. detection of gene diagnosis group 33 cases were detected 23, 67 mutations, most concentrated in exons 1,4,8. were found in 11 known pathogenic mutations, respectively. C.1400CG (p.S467C) c.760CT (p.R254X), c.51CG (p.F17L), c.865CT (p.R289X), c.1195C T (p.R399W), c.338GA (p.C113Y), c.845GA (p.R282Q), c.428CT (p.P143L), c.1433CT (p.P478L) cc.505CT (p.R169W), c.652+1GA, and 12 kinds of new mutations, c.308TG (p.V103G), c.1505CA (p.T502K), c.1445AG (p.Y482C). C.538CG (p.Q180E), c.1427TC (p.L476P), c.40TA (p.W14R), c.1362T G (p.Y454X), C.1252CT (p.Q418X), c.42GA (p.W14X), c.498-2AG, c.507de1G (p.R169RfsX5), c.252_265dup14 (p.I89TfsX46). Among them, the most common mutation sites of c.1400CG (p.S467C), the frequency of about 34.3%; followed by c.760CT (p.R254X) (19.4%) and c.51CG (p.F17L) (11.9%).
The 3. group carrying gene detection in 6 cases, mothers were detected 4, 12 mutations, including 1 novel mutations of c.497+1GT and 3 known pathogenic mutations of c.1400CG (p.S467C), c.760CT (p.R254X) and c.51CG (p.F17L); the most common mutations of c.1400CG (p.S467C), the frequency of 75%.6 infants in 4 cases with c.1400CG (p.S467C) mutation, 2 cases were with c.51CG (p.F17L), c.760CT (p.R254X) c.1400CG (p.S467C) mutation; mutation is still the most common mutations, the frequency of about 66.7%.
4. the initial screening (hereinafter referred to as screening), the mean plasma CO level diagnosis groups for [(7.70 + 2.70) mol/L], carrying Group [(6.43 + 2.33) mol/L], were lower than normal, but no significant difference between groups (P0.01). Diagnosis group before treatment plasma CO level was the decline, increased while carrying a group, there are significant differences between the two (p=0.000). The recovery time, diagnosis group (median 32 days) was significantly longer than that of carrier group (median 26 days) (p=0.000).
5. patients in the 5. confirmed group had 8 cases of loss of visit, 2 cases of interruption treatment, no symptoms related to any other, 16 cases of the mother with leg acid, fatigue, hypoglycemia and other symptoms.
6. of the 6. confirmed patients were detected in 4 of their siblings, the results were 2 cases and 2 were carriers.
7. in addition to those who lost the interview, the average time of follow-up in the diagnosis group was 19.7 months. The patients who took the medicine regularly and regularly reviewed had good prognosis. In the.2 group, 1 cases died suddenly, and 1 cases had Rees syndrome encephalopathy after infection.
8. homozygous mutations were not significantly different from heterozygous mutations in the initial screening of plasma CO level, recovery time and clinical manifestations (P0.01).
Conclusion:
1. primary carnitine deficiency is one of the most common disorders of fatty acid metabolism. The prevalence rate of newborn infants in this province is higher than that of the present literature.
2. most of the mutations in exon 1,4,8, accounting for all the mutations of 77.6%., c.1400C G (p.S467C), c.760CT (p.R254X), c.51CG (p.F17L) mutation is the most common neonatal PCD gene mutations, accounting for about 65.6% of all mutations (were 34.3%, 19.4%, 11.9%).C.1400CG (p.S467C) mutation mother PCD were the most common mutations (75%).
3., the CO level of newborn infants was not able to distinguish the PCD from the carriers, but the plasma CO level was normal or slightly below the normal level. The plasma C0 decreased before medication and the recovery time was long after treatment. All these factors were the strong basis for the diagnosis of PCD.
4. early detection, standardized treatment, long-term follow-up patients have good prognosis, discontinuation of treatment can induce serious clinical events.
5. the correlation between genotypes and phenotype was not found in neonatal PCD patients.

【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2015
【分類號】：R722.1

【共引文獻(xiàn)】

相關(guān)期刊論文 前10條

1 黃曉春;;深圳市新生兒疾病篩查項目實施十年情況回顧[J];當(dāng)代醫(yī)學(xué);2009年10期

2 江劍輝,馬燮琴;遺傳性代謝疾病的篩查診斷新進展[J];廣東醫(yī)學(xué);2002年05期

3 許永福;饒志;;串聯(lián)質(zhì)譜技術(shù)在新生兒遺傳性代謝疾病篩查中的應(yīng)用進展[J];甘肅醫(yī)藥;2012年11期

4 孫增賢;藍(lán)菊紅;;新生兒原發(fā)性肉堿缺乏癥1例[J];中國當(dāng)代兒科雜志;2013年01期

5 范歆;陳少科;羅靜思;李旺;林飛;羅超;耿國興;;串聯(lián)質(zhì)譜技術(shù)在廣西南寧地區(qū)遺傳代謝病篩查中的應(yīng)用[J];廣西醫(yī)科大學(xué)學(xué)報;2013年05期

6 程超;張雪元;李玖軍;;原發(fā)性肉堿缺乏癥1例報告[J];中國當(dāng)代兒科雜志;2014年09期

7 黃玲玲;梁霞;牛曼曼;;新生兒時期起病的遺傳性代謝病2例并文獻(xiàn)復(fù)習(xí)[J];安徽醫(yī)藥;2014年12期

8 曹琴英;張寧;葛軍;朱俊真;趙麗娟;高虹;;遺傳性代謝病篩查救治新模式分析[J];河北醫(yī)藥;2011年24期

9 廖相云;串聯(lián)質(zhì)譜在新生兒篩查中應(yīng)用進展[J];臨床兒科雜志;2003年04期

10 黃倬;韓連書;;原發(fā)性肉堿缺乏癥診治進展[J];臨床兒科雜志;2012年09期

相關(guān)博士學(xué)位論文 前2條

1 李寧;疾病代謝物的色譜—質(zhì)譜分析方法研究[D];復(fù)旦大學(xué);2008年

2 羅斌;細(xì)胞因子信號抑制物-3在脂肪酸β氧化中的作用[D];武漢大學(xué);2013年

相關(guān)碩士學(xué)位論文 前10條

1 蔡燕娜;串聯(lián)質(zhì)譜檢測正常兒童干血濾紙片中游離肉堿和�；鈮A含量[D];廣州醫(yī)學(xué)院;2011年

2 趙基源;色質(zhì)聯(lián)用應(yīng)用于代謝疾病標(biāo)志物的研究[D];清華大學(xué);2005年

3 涂文軍;液相串聯(lián)質(zhì)譜篩查高危兒和新生兒重癥監(jiān)護室患兒遺傳代謝病研究[D];中國協(xié)和醫(yī)科大學(xué);2010年

4 白志梅;4℃平衡時間、甘油和抗氧化劑對豬精液冷凍保存效果的研究[D];西北農(nóng)林科技大學(xué);2013年

5 劉磊;長期口服過量左旋肉堿對健康成年SD大鼠正常代謝的干擾作用[D];南京大學(xué);2012年

6 饒姣;兒童心肌病的遺傳代謝病因分析及相關(guān)研究[D];南方醫(yī)科大學(xué);2014年

7 劉潔欣;人血中氨基酸及肉堿定量檢測和多肽藥物的質(zhì)量控制[D];中國人民解放軍軍事醫(yī)學(xué)科學(xué)院;2014年

8 關(guān)陽;惡性血液病化療患者血漿氨基酸動態(tài)監(jiān)測及營養(yǎng)評價方法的研究[D];第三軍醫(yī)大學(xué);2014年

9 王琚;染鎘大鼠肝腎尿酸系統(tǒng)與脂代謝異常及槲皮素保護作用機制研究[D];南京大學(xué);2012年

10 趙芬;脂質(zhì)沉積性肌病1家系的臨床、病理、生化、基因分析[D];吉林大學(xué);2015年

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