Phenylalanine Hydroxylase Deficiency: Response to BH4
Phenylalanine Hydroxylase Deficiency: Response to BH4
批准号:
6362083
负责人:
REUBEN MATALON
金额:
$7.45万
依托单位国家:
美国
项目类别:
财政年份:
2001
资助国家:
美国
项目状态:
已结题
起止时间:
2001-08-01 至 2003-07-31
关键词:
blood tests enzyme deficiency gene expression gene mutation genetic screening genotype human subject human therapy evaluation inborn aminoacid metabolism disorder medical outreach /case finding metabolism metabolism disorder chemotherapy patient oriented research phenotype phenylalanine 4 monooxygenase phenylketonurias pteridines site directed mutagenesis tetrahydrobiopterin urinalysis
中文摘要
描述(申请人提供):苯丙酮尿症(PKU),因
苯丙氨酸羟化酶(PAH)缺乏症可通过限制饮食来治疗
苯丙氨酸(Phe)。限制Phe饮食治疗PKU已获成功
很难,而且往往不可能达到理想的血液Phe水平
很多病人。报告显示,学校表现不佳,智商下降,以及
当饮食放松时,大脑中的白质恶化。此外,
没有达成一致的随访标准以及血液Phe水平需要什么
在年龄较大的儿童和成年人中进行追踪。另一个复杂的因素是
怀有PKU的孕妇,其后代有神经缺陷的风险
和先天性心脏缺陷。最近,一些PAH缺乏症患者
已发现对大剂量四氢生物蝶呤(BH4)有反应。
四氢生物蝶呤是多环芳烃活性所必需的辅因子。的报道
对BH4反应的PAH缺乏提示PAH的Km突变,而
BH4代谢正常。对这些患者的PAH分析显示不同的
突变,这表明可能存在广泛的PAH突变
应该对BH4做出回应。这项初步研究旨在调查一个多年来
疗程两年,观察PKU患者对BH4负荷的反应。这个
将研究BH4的代谢,确定PAH的突变,以及
将通过现场监测血液Phe水平来研究对BH4的反应
存在时的定向突变、酶表达和酶动力学
不同水平的BH4。PKU体外表达的早期研究
突变的目的不是为了识别对BH4有反应的突变,所以这样
目前还没有关于PAH大约400个突变的数据。取得的成功
这些研究将为许多患者的治疗带来新的研究
并对PAH的突变进行了系统的新研究,以便
确定哪些突变对BH4有反应。用BH4治疗应该会导致
对PKU患者和母体PKU有更好的结局。
英文摘要
DESCRIPTION (provided by applicant): Phenylketonuria (PKU), due to
phenylalanine hydroxylase (PAH) deficiency, is treated by dietary restriction
of phenylalanine (Phe). Treatment of PKU with Phe-restricted diet has been
difficult and often not possible to achieve the desired level of blood Phe for
many patients. Reports indicate poor school performance, loss of IQ, and
white matter deterioration in the brain when diet is relaxed. Furthermore,
there is no agreed upon criteria for follow up and what blood Phe levels need
to be pursued in older children and adults. Another complicating factor is
pregnancy with PKU, which is at risk for offspring with neurological deficits
and congenital heart defects. Recently, some patients with PAH deficiency
have been found to respond to high doses of tetrahydrobiopterin (BH4).
Tetrahydrobiopterin is a cofactor required for PAH activity. The reports of
PAH deficiency responding to BH4 suggest Km mutations of PAH while the
metabolism of BH4 is normal. Analysis of PAH in these patients showed various
mutations, suggesting that there may be a wide range of PAH mutations that
should respond to BH4. This pilot study is intended to investigate, over a
period of two years, patients with PKU and their response to BH4 loading. The
metabolism of BH4 will be studied, mutations of PAH will be determined, and
the response to BH4 will be studied by monitoring blood Phe levels, in situ
directed mutagenesis, enzyme expression, and enzyme kinetics in the presence
of varying levels of BH4. Earlier studies of in vitro expression of PKU
mutations were not aimed to identify mutations that respond to BH4, so such
data are not available on approximately 400 mutations of PAH. Success of
these studies will lead to new research on the treatment for many patients
with PKU, and for a systematic new study of the mutations of PAH in order to
identify which mutations respond to BH4. Treatment with BH4 should lead to a
better outcome for PKU patients and for maternal PKU.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
RESPONSE OF PHENYLKETONURIA TO TETRAHYDROBIOPTERIN (BH4)
-
批准号:7095738
-
项目类别:
-
资助金额:$37.34万
-
财政年份:2005
-
负责人:REUBEN MATALON
-
依托单位:
RESPONSE OF PHENYLKETONURIA TO TETRAHYDROBIOPTERIN (BH4)
-
批准号:7459502
-
项目类别:
-
资助金额:$33.39万
-
财政年份:2005
-
负责人:REUBEN MATALON
-
依托单位:
RESPONSE OF PHENYLKETONURIA TO TETRAHYDROBIOPTERIN (BH4)
-
批准号:7458132
-
项目类别:
-
资助金额:$37.04万
-
财政年份:2005
-
负责人:REUBEN MATALON
-
依托单位:
Phenylalanine Hydroxylase Deficiency: Response to BH4
-
批准号:6526918
-
项目类别:
-
资助金额:$7.45万
-
财政年份:2001
-
负责人:REUBEN MATALON
-
依托单位:
KNOCKOUT MODEL FOR CANAVAN DISEASE
-
批准号:6188111
-
项目类别:
-
资助金额:$27.57万
-
财政年份:1999
-
负责人:REUBEN MATALON
-
依托单位:
KNOCKOUT MODEL FOR CANAVAN DISEASE
-
批准号:2833675
-
项目类别:
-
资助金额:$21.58万
-
财政年份:1999
-
负责人:REUBEN MATALON
-
依托单位:
KNOCKOUT MODEL FOR CANAVAN DISEASE
-
批准号:6394109
-
项目类别:
-
资助金额:$28.6万
-
财政年份:1999
-
负责人:REUBEN MATALON
-
依托单位:
KNOCKOUT MODEL FOR CANAVAN DISEASE
-
批准号:6348802
-
项目类别:
-
资助金额:$5.0万
-
财政年份:1999
-
负责人:REUBEN MATALON
-
依托单位:
KNOCKOUT MODEL FOR CANAVAN DISEASE
-
批准号:6322791
-
项目类别:
-
资助金额:$2.5万
-
财政年份:1999
-
负责人:REUBEN MATALON
-
依托单位:
EFFECTS OF ASPARTAME INTAKE ON PHENYLKETONURIA CARRIERS
-
批准号:3316369
-
项目类别:
-
资助金额:$1.57万
-
财政年份:1985
-
负责人:REUBEN MATALON
-
依托单位:
EFFECTS OF ASPARTAME INTAKE ON PHENYLKETONURIA CARRIERS
-
批准号:3316370
-
项目类别:
-
资助金额:$10.69万
-
财政年份:1985
-
负责人:REUBEN MATALON
-
依托单位:
EFFECTS OF ASPARTAME INTAKE ON PHENYLKETONURIA CARRIERS
-
批准号:3316365
-
项目类别:
-
资助金额:$11.4万
-
财政年份:1985
-
负责人:REUBEN MATALON
-
依托单位:
EFFECTS OF MATERNAL PKU ON PREGNANCY OUTCOME
-
批准号:3650834
-
项目类别:
-
资助金额:$3.34万
-
财政年份:1984
-
负责人:REUBEN MATALON
-
依托单位:
EFFECTS OF MATERNAL PKU ON PREGNANCY OUTCOME
-
批准号:3650835
-
项目类别:
-
资助金额:$20.99万
-
财政年份:1984
-
负责人:REUBEN MATALON
-
依托单位:
EFFECTS OF MATERNAL PKU ON PREGNANCY OUTCOME
-
批准号:3650839
-
项目类别:
-
资助金额:$13.7万
-
财政年份:1984
-
负责人:REUBEN MATALON
-
依托单位:
EFFECTS OF MATERNAL PKU ON PREGNANCY OUTCOME
-
批准号:3650841
-
项目类别:
-
资助金额:$0.0万
-
财政年份:1984
-
负责人:REUBEN MATALON
-
依托单位:
EFFECTS OF MATERNAL PKU ON PREGNANCY OUTCOME
-
批准号:3650844
-
项目类别:
-
资助金额:$0.0万
-
财政年份:1984
-
负责人:REUBEN MATALON
-
依托单位:
EFFECTS OF MATERNAL PKU ON PREGNANCY OUTCOME
-
批准号:3650838
-
项目类别:
-
资助金额:$6.5万
-
财政年份:1984
-
负责人:REUBEN MATALON
-
依托单位:
EFFECTS OF MATERNAL PKU ON PREGNANCY OUTCOME
-
批准号:3650845
-
项目类别:
-
资助金额:$7.79万
-
财政年份:1984
-
负责人:REUBEN MATALON
-
依托单位:
EFFECTS OF MATERNAL PKU ON PREGNANCY OUTCOME
-
批准号:3650832
-
项目类别:
-
资助金额:$15.63万
-
财政年份:1984
-
负责人:REUBEN MATALON
-
依托单位:
海外基金