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目的探讨四氢生物蝶呤反应性苯丙氨酸羟化酶(PAH)缺乏症这一新的临床变异型在高苯丙氨酸血症(HPA)中的发生率,并进一步了解其PAH基因突变类型。方法2001年1月至2004年12月,上海第二医科大学附属新华医院收治的106例中位年龄2个月(0.5～59个月)的HPA患儿纳入研究。所有患儿做辅酶的羟生物蝶呤(BH4,20mg/kg)或联合血苯丙氨酸(Phe,100mg/kg)负荷试验、尿蝶呤谱分析及红细胞二氢蝶啶还原酶活性(DHPR)测定。以口服BH4后24h内血Phe浓度下降30%以上且排除BH4缺乏症为诊断标准。对13例BH4反应性PAH缺乏症患儿进行PAH基因突变检测。结果106例HPA者中41例(38.7%)为BH4反应性的PAH缺乏症。血Phe浓度在服用BH4前为(816±431)μmol/L,服BH4后24h内降至(267±198)μmol/L,反应下降率(67±19)%。41例尿蝶呤及DHPR活性均正常。106例中轻度HPA(18例)其BH4反应性PAH缺乏症发生率为61.1%(11/18)。13例做PAH基因突变检测,R241C为最多见突变类型(43.8%)。结论61.1%轻度HPA(11/18)及42.4%(28/66)轻度PKU对BH4有较大反应性。BH4负荷试验是该病有效而简便的鉴别诊断方法。     

不同类型高苯丙氨酸血症的临床表型

目的探讨不同类型高苯丙氨酸血症（HPA）临床表型,了解HPA患者对低苯丙氨酸（Phe）饮食治疗的反应性。方法HPA患儿44例均口服四氢生物喋呤（BH4）负荷试验（20 mg/kg）或Phe-BH4联合负荷试验,同时进行尿喋呤谱分析、红细胞二氢喋呤还原酶（DHPR）测定。治疗前采用Gesell发育量表进行智力测定并行脑电图检查。予苯丙氨酸羟化酶（PAH）缺乏症患者低Phe饮食治疗,控制血Phe在120~360μmol/L,监测Phe耐受量。结果1.确诊BH4反应性PAH缺乏症患儿12例。男7例,女5例;平均年龄7.8个月;生化代谢表型均为轻度或中度HPA。2.部分BH4缺乏症患儿确诊前经低Phe饮食治疗后血Phe可以控制在较低水平,但仍出现进行性神经损害,脑电图异常率为72.7%。3.BH4反应性PAH缺乏症的发育商明显高于其他HPA;饮食治疗中的Phe耐受量较高。结论BH4反应性PAH缺乏症患者对饮食治疗的反应性更好。早期BH4缺乏症的鉴别诊断非常重要。     

四氢生物蝶呤反应性苯丙氨酸羟化酶缺乏症

目的：四氢生物蝶呤(BH4)可以使BH4缺乏症病人的血液苯丙氨酸水平正常化,但是对苯丙酮酸尿症(PKU)病人无效。最近在新生儿PKU筛查中发现了对BH4有反应的轻度PKU患者。本研究将探讨BH4和苯丙氨酸羟化酶(PAH)基因突变在对BH4有反应的轻度PKU和轻度高苯丙酸血症(HPA)患者中的作用。方法：对经新生儿PKU筛查中发现的生物蝶呤代谢正常的轻度HPA患者,进行单次(10mg/kg)、4次、1周[20 mg/(kg·d)]的BH4口服负荷试验及长期BH4治疗,评估其对BH4口服负荷试验的反应性。结果：在单剂量BH4口服负荷试验中,典型PKU患者的血苯丙氨酸水平没有降低。在单剂量BH4口服负荷试验中血苯丙氨酸水平下降超过20%的患者,在4次BH4口服负荷试验中下降亦超过20%。1周BH4负荷试验确认在单剂量和4次BH4负荷试验中表现出弱反应性的病人对BH4有反应。许多患轻度PKU和轻度HPA且有R241C基因位点的病人,都对BH4治疗有反应。在无BH4反应性的典型PKU病人中未发现R241C、P407S和A373T基因突变。结论：1周BH4负荷试验用于诊断BH4反应性PAH缺乏症最为有效。等位基因R241C、P407S和A373T与轻度HPA和轻度PKU病人具有H4反应性有关。BH4治疗是针对轻度HPA和轻度PKU的一种新颖、有效的药物治疗,有望代替限制苯丙氨酸饮食的方法。     

四氢生物蝶呤负荷试验诊断四氢生物蝶呤反应性苯丙氨酸羟化酶缺乏症的临床研究

目的探讨四氢生物蝶呤(BH4)反应性苯丙氨酸羟化酶(PAH)缺乏症的临床诊断方法,进一步了解其临床特征,为该型患儿应用BH4药物治疗提供科学依据。方法73例高苯丙氨酸血症(HPA)患儿,男47例,女26例,平均年龄1.93个月。所有患儿都进行口服BH4负荷试验,同时进行尿蝶呤谱分析、红细胞二氢蝶啶还原酶测定。对其中血苯丙氨酸(Phe)浓度<600μmol/L者给予口服Phe BH4联合负荷试验,对部分BH4反应性PAH缺乏症患儿,在普食条件下给予BH4片剂(10～20mg/kg)替代治疗6～7天,观察其疗效。结果(1)在BH4负荷试验中,不同类型HPA患儿的血Phe浓度表现出特征性的曲线改变,22例诊断为经典型苯丙酮尿症(PKU),39例中度PKU,12例四氢生物蝶呤缺乏症;(2)在中度PKU患儿中发现22例(56.4%)对BH4有反应;(3)6例BH4反应性PAH缺乏症患儿以BH410mg/kg治疗6～7天,其中4例血Phe浓度能控制到正常或接近正常治疗水平,另2例BH4需增加到20mg/kg使Phe浓度显著下降。结论在BH4负荷试验中,部分因苯丙氨酸羟化酶缺乏引起的中轻度PKU患儿对BH4有反应性,给予这些患儿BH4治疗可部分或全部替代低苯丙氨酸饮食治疗,拓宽了PKU的治疗方法,有助于提高患儿的生活质量。     

宁夏苯丙酮尿症患儿苯丙氨酸羟化酶基因外显子7突变分析

目的 探讨宁夏地区苯丙酮尿症（PKU）患儿苯丙氨酸羟化酶（PAH）基因外显子7 突变类型及频率,为该地区PKU 的基因诊断和产前诊断提供依据。方法 应用PCR 产物直接测序方法,对宁夏73 例经典型PKU 患儿（回族39 例,汉族34 例）的146 个PAH 等位基因外显子7 及其旁侧内含子区域进行序列分析。结果 共检测出6 种突变基因型,分别是R243Q（14.4%）、R241C（6.8%）、IVS7+2T → A（2.7%）、L255S（0.7%）、G247V（0.7%）和G247R（0.7%）。外显子7 突变基因总频率为26.0%（38/146）,包括错义突变和剪接位点突变两种。回族患儿R241C 等位基因突变检出率高于汉族（10% vs 3%,P<0.05）。结论 宁夏地区PKU 患儿PAH 基因外显子7 突变频率最高的是R243Q,其次为R241C;回族和汉族PKU 患儿R241C 等位基因突变率不同。     

四氢生物蝶呤反应性苯酮尿症的研究进展

四氢生物蝶呤（BH4）反应性苯酮尿症是苯丙氨酸羟化酶（PAH）基因突变导致PAH活性降低，且患者服用BH4后24h内血苯丙氨酸（Vhe）浓度较服药前下降30％或以上的一种特殊类型。该文探讨了BH4反应性PAH缺乏症的基因型及其与表型的关系、发生机制、诊断和治疗研究进展。BH4可部分或完全替代低苯丙氨酸饮食治疗，为苯酮尿症个体化治疗提供了新途径。     

苯丙氨酸羟化酶缺乏症基因型与表型的关系

目的研究江苏地区苯丙氨酸羟化酶缺乏症(PAHD)患儿的基因突变特点,构建本地区苯丙氨酸羟化酶(PAH)基因突变谱,讨论PAHD基因型与表型的关系。方法应用基因测序技术对70例PAHD患儿及其父母进行PAH基因第1~13外显子及两侧内含子序列分析。结果 70例患儿的140个等位基因中125个检测出突变,检出率为89.29%,常见突变依次为EX6-96AG(19/125,15.20%),R243Q(18/125,14.40%)和R241C(17/125,13.60%)。经典型苯丙酮尿症(PKU)患儿最常见突变为R243Q和EX6-96AG,共占42.86%中度PKU患儿最常见突变为EX6-96AG,R241C和R111X,共占40.74%;轻度PKU患儿最常见的突变是R241C,EX6-96AG和R243Q,共占57.89%;轻度HPA患儿最常见的突变是R241C和R243Q,共占40.00%。通过基因型预测的生化表型与患儿实际生化表型一致率为65.63%,其中经典型PKU的预测一致率较高,为81.25%;预测生化表型(即AV值评分)与患儿治疗前血苯丙氨酸水平呈显著负相关(r=-0.77,P0.001)。结论江苏地区PAH基因突变谱与其他地区有所不同,基因型与表型之间存在一定的联系。     

苯丙酮尿症患者32例家系基因突变研究北大核心CSCD

目的：检测苯丙酮尿症（PKU）患儿及其父母苯丙氨酸羟化酶（PAH）基因突变谱,并探讨 PAH 基因突变与临床严重程度的相关性,为本地区 PKU 患儿的早期诊断及遗传咨询提供基础数据。方法使用高通量测序技术对来自江苏省无锡和宿迁的32例 PKU 患儿及其父母的 PAH 基因13个外显子及其附近内含子区域进行测序分析。结果32例 PKU 共检测出61个突变位点,33种突变基因,突变检出率为95.31％（61/64个）。本地区 PKU 患儿常见致病突变位点为 c.721C ﹥ T、c.1068C ﹥ A、c.611A ﹥ G、c.1197A ﹥ T、c.728G ﹥ A、c.331C ﹥ T 和 c.442-1G ﹥ A,其突变频率均在5％以上。首次报道1个新的突变基因位点 c.699C ﹥ G 和3个汉族人口中新的突变基因位点 c.265C ﹥ T、c.722G ﹥ A 和 c.1194A ﹥ G。Guldberg AV 系统分析显示38.0％（8/21例）的 PKU 患者基因型与实际生化表型相一致,其中预测表型为中重度的与实际生化表型的一致率为92.3％（12/13例）,轻度的与实际生化表型的一致率为50.0％（4/8例）。结论江苏地区 PKU 患儿的 PAH 基因突变集中在外显子7上,其中频率最高的基因位点是 c.721C ﹥ T,并首次发现1个新的基因突变位点 c.699C ﹥ G;PKU 患者基因型与生化表型之间有一定的相关性。     

青岛地区6-丙酮酰四氢生物蝶呤缺乏症患儿基因变异特点及随访分析

目的 探讨青岛地区6-丙酮酰四氢蝶呤合成酶缺乏症（PTPSD）筛查情况、临床表现、基因变异情况及长期随访结果。方法 对1996年11月至2021年12月经新生儿筛查确诊的251例高苯丙氨酸血症（HPA）患儿进行尿蝶呤谱检测、红细胞二氢蝶呤还原酶活性检测、四氢生物蝶呤（BH4）负荷试验及基因检测以确诊PTPSD，进一步分析青岛市PTPSD的发生率、基因变异特点及长期随访结果。结果 251例HPA患儿中，26例诊断为四氢生物蝶呤缺乏症（2对单卵双胞胎、1对为非同胎生姐妹），均为PTPSD，发病率为12.7/100万（双胎按1例计算）。19例患儿（来自17个家庭）进行基因检测，PTPS的34个等位基因中共检测出10种变异，变异频率较高的为c.259C>T(29.4%,10/34)，其余依次为c.286G>A(14.7%,5/34)、c.272A>G(14.7%,5/34)、c.84-291A>G(8.8%,3/34)、c.166G>A(8.8%,3/34)、c. 276 T>A(8.8%,3/34)，变异位点主要集中在5号外显子67.6%(23/34)。其...     

四氢生物蝶呤反应性苯酮尿症的研究进展

四氢生物蝶呤(BH4)反应性苯酮尿症是苯丙氨酸羟化酶(PAH)基因突变导致PAH活性降低,且患者服用BH4后24h内血苯丙氨酸(Phe)浓度较服药前下降30%或以上的一种特殊类型。该文探讨了BH4反应性PAH缺乏症的基因型及其与表型的关系、发生机制、诊断和治疗研究进展。BH4可部分或完全替代低苯丙氨酸饮食治疗,为苯酮尿症个体化治疗提供了新途径。     

In vivo studies of phenylalanine hydroxylase by phenylalanine breath test: diagnosis of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency

Tetrahydrobiopterin (BH4)-responsive phenylalanine hydroxylase (PAH) deficiency is characterized by reduction of blood phenylalanine level after a BH4-loading test. Most cases of BH4-responsive PAH deficiency include mild phenylketonuria (PKU) or mild hyperphenylalaninemia (HPA), but not all patients with mild PKU respond to BH4. We performed the phenylalanine breath test as reliable method to determine the BH4 responsiveness. Phenylalanine breath test quantitatively measures the conversion of L-[1-13C] phenylalanine to 13CO2 and is a noninvasive and rapid test. Twenty Japanese patients with HPA were examined with a dose of 10 mg/kg of 13C-phenylalanine with or without a dose of 10 mg . kg(-1) . d(-1) of BH4 for 3 d. The phenylalanine breath test [cumulative recovery rate (CRR)] could distinguish control subjects (15.4 +/- 1.5%); heterozygotes (10.3 +/- 1.0%); and mild HPA (2.74%), mild PKU (1.13 +/- 0.14%), and classical PKU patients (0.29 +/- 0.14%). The genotypes in mild PKU cases were compound heterozygotes with mild (L52S, R241C, R408Q) and severe mutations, whereas a mild HPA case was homozygote of R241C. CRR correlated inversely with pretreatment phenylalanine levels, indicating the gene dosage effects on PKU. BH4 loading increased CRR from 1.13 +/- 0.14 to 2.95 +/- 1.14% (2.6-fold) in mild PKU and from 2.74 to 7.22% (2.6-fold) in mild HPA. A CRR of 5 to 6% reflected maintenance of appropriate serum phenylalanine level. The phenylalanine breath test is useful for the diagnosis of BH4-responsive PAH deficiency and determination of the optimal dosage of BH4 without increasing blood phenylalanine level.     

Long-term treatment and diagnosis of tetrahydrobiopterin-responsive hyperphenylalaninemia with a mutant phenylalanine hydroxylase gene

A novel therapeutic strategy for phenylketonuria (PKU) has been initiated in Japan. A total of 12 patients who met the criteria for tetrahydrobiopterin (BH(4))-responsive hyperphenylalaninemia (HPA) with a mutant phenylalanine hydroxylase (PAH) (EC 1.14.16.1) gene were recruited at 12 medical centers in Japan between June 1995 and July 2001. Therapeutic efficacy of BH(4) was evaluated in single-dose, four-dose, and 1-wk BH(4) loading tests followed by long-term BH(4) treatment, and also examined in relation to the PAH gene mutations. The endpoints were determined as the percentage decline in serum phenylalanine from initial values after single-dose (>20%), four-dose (>30%), and 1-wk BH(4) (>50%) loading tests. Patients with mild PKU exhibiting decreases in blood phenylalanine concentrations of >20% in the single-dose test also demonstrated decreases of >30% in the four-dose test. The 1-wk test elicited BH(4) responsiveness even in patients with poor responses in the shorter tests. Patients with mild HPA, many of whom carry the R241C allele, responded to BH(4) administration. No clear correlation was noted between the degree of decrease in serum phenylalanine concentrations in the single- or four-dose tests and specific PAH mutations. The 1-wk test (20 mg/kg of BH(4) per day) is the most sensitive test for the diagnosis of BH(4)-responsive PAH deficiency. Responsiveness apparently depends on mutations in the PAH gene causing mild PKU, such as R241C. BH(4) proved to be an effective therapy that may be able to replace or liberalize the phenylalanine-restricted diets for a considerable number of patients with mild PKU.     

Assessment of tetrahydrobiopterin responsiveness in Turkish hyperphenylalaninemic patients

Tetrahydrobiopterin (BH4) therapy is the latest alternative approach in phenylalanine hydroxylase (PAH) deficiency, and is suggested for a number of hyperphenylalaninemic (HPA) patients with certain mutations. In our unit, therapeutic efficacy of BH4 was evaluated in 20 HPA patients (4 mild HPA, 9 mild phenylketonuria-PKU, 7 moderate PKU) by a single oral dose of BH4. Overall, 60% of the patients responded (45% favorably, 15% partially). All of the mild HPA patients and 55% of mild PKU patients responded to BH4 favorably and an additional 11% of mild PKU patients responded partially. Of 7 moderate PKU patients, 2 responded partially (28%). The genotypes of the patients who responded to BH4 favorably were: DelF39/-, L48S/L48S, R261Q/- (4 patients), A300S/IVS2nt5g > c, A300S/-, E390G/E390G. The genotypes of the patients who exhibited a partial response were: L48S/L48S, R261Q/ R261Q, IVS10nt546/-. We concluded that since there are too many mutations and many patients are compound heterozygote, it is difficult to predict BH4 responsiveness based solely on genotype, especially for the mutations which show inconsistent phenotypes. The best way to identify the patients who are more likely to benefit from BH4 administration is performing BH4 loading test. Long-term BH4 loading test should be performed in classical and moderate PKU patients to confirm that they are not responsive to BH4.     

苯丙酮尿症患儿苯丙氨酸羟化酶基因突变的研究

目的了解宁夏地区苯丙酮尿症(PKU)儿童苯丙氨酸羟化酶(PAH)基因突变的特征。方法以经新生儿疾病筛查及气相色谱-质谱联用技术确诊的30例宁夏PKU儿童为病例组,30例正常儿童为对照组,应用PCR技术扩增PAH基因的3、5、6、7、11和12,六个外显子,再经单链构象多态性分析和DNA测序分析PCR扩增产物。结果在60个等位基因中检出51个突变基因,检出率85%;六个外显子共检出16种致病突变,包括8种错义突变(R241C、R243Q、R252Q、G 257 V、R359K*、R408Q、R 413 P、Q419R),3种剪接突变(IVS 4-1 GA、Y 204 C、IVS 7+2 TA),3种无义突变(R 111 X、Q160X、Y356X),1种同义突变(V399V)和1种缺失突变(N183del);R243Q突变频率最高,检出率为18.3%,其次是Y 204 C(11.7%)、IVS 4-1 GA(10.0%)、R 111 X(6.7%)和IVS 7+2 TA(6.7%)。病例组中发现Exon 6的N183del(C.547-549del GAA)缺失突变和Exon 11的R359K(C.1078GA)错义突变,为国内首次发现;病例组和对照组中均检出V245V(C.735GA)和Q232Q(C.696AG)两种静止突变,且差异无统计学意义(P0.05)。结论宁夏PKU儿童PAH基因六个外显子最常见的突变类型是错义突变,特别是R243Q;发现中国人群PAH基因的2种新的突变。     

Evaluation of neonatal BH4 loading test in neonates screened for hyperphenylalaninemia

Background

The outcome in phenylketonuria is related to the early diagnosis and management due to neonatal screening.

Aims

To assess the interest of tetrahydrobiopterin (BH4) loading test and phenylalanine hydroxylase (PAH) genotyping in the management of neonates with hyperphenylalaninemia (HPA).

Study design

We evaluate the effectiveness of a BH4 loading test (20 mg/kg) in ten neonates screened for HPA. We evaluated the time required to reach a target plasma Phenylalanine (Phe) level below 300 µmol/l. We compared these ten BH4-loaded patients to the 10 previous neonates non-loaded with BH4. In all these patients, the PAH genotype was determined.

Results

One loaded patient had biopterin synthesis deficiency and has been retrieved from statistical analysis. All others patients have PAH deficiency. Between the BH4 loaded group (L) and the BH4 non-loaded group (NL), a statistically significant difference was observed in the average time required to reached the target Phe level (13.56 ± 4.30 (L) vs. 20.6 ± 7.59 days (NL) [p < 0.02]). Results of the genotyping from all but one of these 19 patients indicated that among all mutations present in this patient population, there were 4 known PAH mutations associated with BH4 responsiveness (p.R261Q, the p.V388 M, the p.E390G and the p.Y414C). These mutations were found in 4 non-loaded and 6 loaded patients. Two patients had a more than 90% reduction in their plasma Phe level within 24 h after the load. One of these patients had a PTPS deficiency. The other fully responsive patient (p.Y414C and IVS10-11G > A) has been treated with BH4 from birth with an excellent metabolic control for three years now.

Conclusion

BH4 loading test improves the management of HPA. It allows an immediate identification of the children fully responsive to BH4. Our results therefore suggest the incorporation of BH4 loading test in the management of neonates screened for HPA.     

Molecular correlations in phenylketonuria: mutation patterns and corresponding biochemical and clinical phenotypes in a heterogeneous California population.

We studied 133 California phenylketonuria (PKU) patients and one obligate heterozygote to delineate the molecular basis of PKU in a population with greater ethnic diversity than in previous studies, and to determine whether a correlation exists between genotype and clinical phenotype, with the latter defined by both the diagnostic pretreatment blood phenylalanine (PHE) level and cognitive (IQ) test scores. To determine PAH genotypes, we used PCR-mediated amplification, denaturing gradient gel electrophoresis, and direct sequencing on dried whole blood samples. Where possible, mutation severity was defined according to predicted in vitro PAH enzyme activity estimated by using Cos cell expression analysis for a given mutation. We then asked whether mutation severity, as defined by such expression analysis, correlated with pretreatment PHE levels or with IQ test results. A mutation was identified in 236 (88%) of 267 mutant alleles. Seventeen new mutant alleles were found; A47E, T81P, I102T, E182G, T328D, Y343P, K371R, Y387H, A389E, E422K, IVS9nt5, IVS11nt20, delS70, del364-368/del198-220, delF299, delT323, and -1C/T. In striking contrast to a number of studies in other populations, in this study, based on predicted PAH activity, we observed no correlation between mutation severity and pretreatment PHE levels. There was also no correlation between genotype and IQ. We conclude that in samples collected from an ethnically heterogeneous population, there is no correlation of mutation severity with either pretreatment PHE levels or IQ measurement in treated patients. We caution that genetic counseling in PKU should incorporate the notion that prognosis may not be predicted with precision based on mutation analysis in a given patient.     

青岛市苯丙氨酸羟化酶缺乏症患儿基因突变分析

目的探讨青岛市苯丙氨酸羟化酶(phenylalanine hydroxylase,PAH)缺乏症患儿的基因突变特点,为青岛市PAH缺乏症的产前诊断、治疗提供科学参考依据。方法对经青岛市新生儿疾病筛查确诊的44例PAH缺乏症患儿,应用第二代高通量测序及多重连接酶探针依赖扩增(multi-ligase probe dependent amplification,MLPA)技术进行基因分析,检测患儿基因突变位点,应用Sanger测序对其父母的PAH基因相应突变位点进行检测并验证。根据患儿血苯丙氨酸浓度,分为经典型苯丙酮尿症、轻度苯丙酮尿症和轻度高苯丙氨酸血症。结果①44例PAH缺乏症患儿PAH基因中均检测到2个突变位点,其中2例为纯合突变,纯合突变的频率为4.6%,所有突变在患儿父母相应突变位点处均能检测到。②44例PAH缺乏症患儿共检测到突变36种,其中c.728G>A突变频率最高(15.9%,14/88),其次是c.1068C>A(10.2%,9/88),再次为c.158G>A(9.1%,8/88)。③21例经典型苯丙酮尿症患儿PAH基因突变19种,其中c.1068C>A突变频率最高(21.4%,9/42),其次是c.728G>A(19.0%,8/42)。10例轻度苯丙酮尿症患儿PAH基因突变14种,其中c.721C>T/722delG突变频率最高(15.0%,3/20),其次为c.1197A>T、c.1301C>A、c.721C>T、c.728G>A(均为10.0%,2/20)。13例轻度高苯丙氨酸血症患儿PAH基因突变17种,其中c.158G>A突变频率最高(26.9%,7/26),其次为c.728G>A(15.4%,4/26)。结论青岛市PAH缺乏症患儿PAH基因突变以复合杂合突变为主,具有明显热点突变(c.728G>A、c.1068C>A、c.158G>A),经典型苯丙酮尿症患儿以c.1068C>A、c.728G>A为主,轻度苯丙酮尿症患儿以c.721C>T/722delG为主,轻度高苯丙氨酸血症患儿以c.158G>A为主。本研究明确了青岛市PAH缺乏症患儿基因的突变类型与特点,为深入开展PAH缺乏症的诊断以及进一步的基因治疗奠定了基础。