更新于：2024-11-01

Hyperphenylalaninemia, BH4-Deficient, B

BH4缺乏的B型高苯丙氨酸血症

更新于：2024-11-01

基本信息

别名

GTP - Guanosine-5-triphosphate cyclohydrolase deficiency、GTP CYCLOHYDROLASE I DEFICIENCY、GTP Cyclohydrolase I Deficiency

+ [16]

简介

An autosomal recessive condition caused by mutation(s) in the GCH1 gene, encoding GTP cyclohydrolase 1. It is characterized by hyperphenylalaninemia and GTP cyclohydrolase 1-deficient dopa-responsive dystonia.

关联

项与 BH4缺乏的B型高苯丙氨酸血症相关的药物

Sapropterin Dihydrochloride

盐酸沙丙蝶呤

靶点

PAH

作用机制

PAH激动剂

在研机构

Dipharma Francis Srl [+5]

原研机构

Daiichi Sankyo Co., Ltd.

在研适应症

BH4缺乏的B型高苯丙氨酸血症 [+4]

非在研适应症

白蛋白尿 [+12]

最高研发阶段批准上市

首次获批国家/地区

日本

首次获批日期1992-03-27

项与 BH4缺乏的B型高苯丙氨酸血症相关的临床试验

NCT03655223 / Enrolling by invitationN/AIIT

Early Check: A Collaborative Innovation to Facilitate Pre-Symptomatic Clinical Trials in Newborns

Early Check provides voluntary screening of newborns for a selected panel of conditions. The study has three main objectives: 1) develop and implement an approach to identify affected infants, 2) address the impact on infants and families who screen positive, and 3) evaluate the Early Check program. The Early Check screening will lead to earlier identification of newborns with rare health conditions in addition to providing important data on the implementation of this model program. Early diagnosis may result in health and development benefits for the newborns. Infants who have newborn screening in North Carolina will be eligible to participate, equating to over 120,000 eligible infants a year. Over 95% of participants are expected to screen negative. Newborns who screen positive and their parents are invited to additional research activities and services. Parents can enroll eligible newborns on the Early Check electronic Research Portal. Screening tests are conducted on residual blood from existing newborn screening dried blood spots. Confirmatory testing is provided free-of-charge for infants who screen positive, and carrier testing is provided to mothers of infants with fragile X. Affected newborns have a physical and developmental evaluation. Their parents have genetic counseling and are invited to participate in surveys and interviews. Ongoing evaluation of the program includes additional parent interviews.

开始日期2018-10-15

申办/合作机构

Research Triangle Institute

[+15]

NCT01425528 / Completed临床1/2期IIT

Pilot Study to Assess Impact of Kuvan® Supplementation as an Adjunct Treatment in Subjects With Dominantly-inherited GTPCH Deficiency on Mood, Behavioral and Motor Phenotypes

The purpose of this study is to identify the dose of Kuvan needed to normalize the levels of tetrahydrobiopterin (BH4) in patients with a Guanosine Triphosphate Cyclohydrolase (GTPCH) deficiency and to asses the potential impact of oral Kuvan on mood and function in individuals with GTPCH deficiency who may be experiencing symptoms of anxiety, depression, fatigue, trouble concentrating, or memory loss. This will be a phase one study. The investigators will monitor patients over a period of three to six months while on the medication. Medication levels will be monitored by measuring the BH4 levels in cerebral spinal fluid (CSF). Patients will undergo a baseline lumbar puncture and two follow-up lumbar punctures for this purpose. The investigators will also monitor emotional function and motor function.

开始日期2011-08-01

申办/合作机构

University of Utah

[+1]

EUCTR2008-005394-35-ES / Not yet recruitingN/AIIT

Tratamiento de la hiperfenilalaninemia con dihidrocloruro de sapropterina (tetrahidrobiopterina, 6R-BH4) y su influencia en el patrón de aminoácidos y ácidos grasos desde la infancia hasta la edad adulta.

开始日期2009-11-10

申办/合作机构-

100 项与 BH4缺乏的B型高苯丙氨酸血症相关的临床结果

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100 项与 BH4缺乏的B型高苯丙氨酸血症相关的转化医学

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0 项与 BH4缺乏的B型高苯丙氨酸血症相关的专利（医药）

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项与 BH4缺乏的B型高苯丙氨酸血症相关的文献（医药）

2024-09-01·Movement Disorders Clinical Practice

Autosomal Recessive Guanosine Triphosphate Cyclohydrolase I Deficiency: Redefining the Phenotypic Spectrum and Outcomes

Review

作者: Bove, Rossella ; Ricciardi, Giacomina ; Novelli, Maria ; Ebrahimi‐Fakhari, Darius ; Pisani, Francesco ; Leuzzi, Vincenzo ; Manti, Filippo ; Quiroz, Vicente ; Yang, Kathryn ; Tolve, Manuela ; Carducci, Claudia ; Galosi, Serena

AbstractBackgroundThe GCH1 gene encodes the enzyme guanosine triphosphate cyclohydrolase I (GTPCH), which catalyzes the rate‐limiting step in the biosynthesis of tetrahydrobiopterin (BH4), a critical cofactor in the production of monoamine neurotransmitters. Autosomal dominant GTPCH (adGTPCH) deficiency is the most common cause of dopa‐responsive dystonia (DRD), whereas the recessive form (arGTPCH) is an ultrarare and poorly characterized disorder with earlier and more complex presentation that may disrupt neurodevelopmental processes. Here, we delineated the phenotypic spectrum of ARGTPCHD and investigated the predictive value of biochemical and genetic correlates for disease outcome.ObjectivesThe aim was to study 4 new cases of arGTPCH deficiency and systematically review patients reported in the literature.MethodsClinical, biochemical, and genetic data and treatment response of 45 patients are presented.ResultsThree phenotypes were outlined: (1) early‐infantile encephalopathic phenotype with profound disability (24 of 45 patients), (2) dystonia‐parkinsonism phenotype with infantile/early‐childhood onset of developmental stagnation/regression preceding the emergence of movement disorder (7 of 45), and (3) late‐onset DRD phenotype (14 of 45). All 3 phenotypes were responsive to pharmacological treatment, which for the first 2 must be initiated early to prevent disabling neurodevelopmental outcomes. A gradient of BH4 defect and genetic variant severity characterizes the 3 clinical subgroups. Hyperphenylalaninemia was not observed in the second and third groups and was associated with a higher likelihood of intellectual disability.ConclusionsThe clinical spectrum of arGTPCH deficiency is a continuum from early‐onset encephalopathies to classical DRD. Genotype and biochemical alterations may allow early diagnosis and predict clinical severity. Early treatment remains critical, especially for the most severe patients.

2024-03-01·European Journal of Pharmacology

Mechanisms underlying the efficacy and limitation of dopa and tetrahydrobiopterin therapies for the deficiency of GTP cyclohydrolase 1 revealed in a novel mouse model

Article

作者: Zheng, Xiaoning ; Liu, Huazhen ; Wang, Meiyi ; Liao, Yongqiang ; Jiang, Xiaoling ; Zeng, Chunhua ; Cai, Yanna ; Shao, Yongxian ; Peng, Minzhi ; Zhang, Wen ; Lin, Yunting ; Liu, Li

Dopa and tetrahydrobiopterin (BH4) supplementation are recommended therapies for the dopa-responsive dystonia caused by GTP cyclohydrolase 1 (GCH1, also known as GTPCH) deficits. However, the efficacy and mechanisms of these therapies have not been intensively studied yet. In this study, we tested the efficacy of dopa and BH4 therapies by using a novel GTPCH deficiency mouse model, Gch1^KI/KI, which manifested infancy-onset motor deficits and growth retardation similar to the patients. First, dopa supplementation supported Gch1^KI/KI mouse survival to adulthood, but residual motor deficits and dwarfism remained. Interestingly, RNAseq analysis indicated that while the genes participating in BH4 biosynthesis and regeneration were significantly increased in the liver, no significant changes were observed in the brain. Second, BH4 supplementation alone restored the growth of Gch1^KI/KI pups only in early postnatal developmental stage. High doses of BH4 supplementation indeed restored the total brain BH4 levels, but brain dopamine deficiency remained. While total brain TH levels were relatively increased in the BH4 treated Gch1^KI/KI mice, the TH in the striatum were still almost undetectable, suggesting differential BH4 requirements among brain regions. Last, the growth of Gch1^KI/KI mice under combined therapy outperformed dopa or BH4 therapy alone. Notably, dopamine was abnormally high in more than half, but not all, of the treated Gch1^KI/KI mice, suggesting the existence of variable synergetic effects of dopa and BH4 supplementation. Our results provide not only experimental evidence but also novel mechanistic insights into the efficacy and limitations of dopa and BH4 therapies for GTPCH deficiency.

2023-04-01·Parkinsonism & Related Disorders

Heterozygous pathogenic variant in GCH1 associated with treatable severe spastic tetraplegia: Expert opinion

作者: Lambert, Laetitia ; Benoist, Jean-Francois ; Ravel, Jean-Marie ; Puisieux, Salome ; Banneau, Guillaume ; Michaud, Maud ; Frismand, Solene ; Renaud, Mathilde ; Bonnet, Celine

GCH1 encodes for GTP cyclohydrolase I and has been historically associated with two disorders: bi-allelic variations are associated with tetrahydrobiopterin (BH4)-deficient hyperphenylalaninemia B (MIM #233910), while heterozygous variations cause autosomal dominant dopa-responsive dystonia (DRD, MIM #128230).Heterozygous GCH1 pathogenic variations have also been described in Parkinson's disease and are known to have incomplete penetrance.Herein, authors report an addnl. patient presenting with a severe HSP, including tetraplegia, harboring a heterozygous GCH1 pathogenic variation.This case is the most severe form of the eight previously reported cases.The case presented highlights the involvement of GCH1 in HSP-mimic presentation, reaching nine reported patients and extending the phenotypical spectrum to very severe forms.As for the other cases, no phenotype-genotype correlation exists to explain clin. diversity and severity.This case report highlights the utility of clin. exome or large panel testing in complex neurol. presentations.This unusual situation represents a rare opportunity for treatment for patients presenting with HSP-mimic symptoms.

项与 BH4缺乏的B型高苯丙氨酸血症相关的新闻（医药）

2023-07-03

·药通社

冲刺获批！山东药企拿下罕见病药首仿！

据6月29日NMPA发布的一批药品批准证明文件显示，鲁南制药集团山东新时代药业有限公司的盐酸沙丙蝶呤片获批上市（商品名：海普益），斩获该品种国内首仿。此前，国内仅拜马林制药BioMarin International Limited持有的原研制剂-盐酸沙丙蝶呤片（科望）上市，目前其注册证已过期，鲁南制药为国内独家获批上市厂家。盐酸沙丙蝶呤片是目前治疗高苯丙氨酸血症这一罕见病的唯一药物，适用于对本品治疗有反应的四氢生物蝶呤（BH4）缺乏症所导致的高苯丙氨酸血症（HPA）。该药物原研于2007年由美国食品药品监督管理局批准上市，2011年获得中国国家市场监督管理总局（原中国食品药品监督管理局）的上市批准，该药物30片装售价大概7480元。2022年，该药物院内销售额约900万元。全国医院销售数据库2021年，北京将其纳入药物报销范围，终身报销60%。去年，拜马林制药宣布，其盐酸沙丙蝶呤片将退出中国市场，原因系国外已有仿制药上市，带来了患者市场的大量流失，从企业整体考量，继续保留该产品线的价值已不大。据药融云数据，原研的盐酸沙丙蝶呤片最新一次再注册为2018年获得批准，有限期至2023年3月21日。此次鲁南制药为盐酸沙丙蝶呤片国内独家获批上市厂家。疾病概览 2018年5月11日，国家卫生健康委员会等5部门联合制定了《第一批罕见病目录》，高苯丙氨酸血症被收录其中。这是一种基因突变或遗传疾病，患儿无法正常代谢苯丙氨酸，如食用普通食物，体内将大量累积，进而产生高苯丙氨酸血症症状，因此也被称作“不食人间烟火的孩子”。血液中高浓度苯丙氨酸会对中枢神经系统造成不可逆损伤，使患者产生智力低下、自闭症、癫痫、运动障碍等临床症状。如果该病得不到及时治疗，会对患者中枢神经系统造成严重的损伤。 2023年国谈启动，它会进医保吗？罕见病药退出市场，不罕见，如此前的意大利外企东沛制药的塞奈吉明滴眼液（欧适维）、百傲万里制药的黏多糖贮积症IVA型特效药唯铭赞（Vimizim，依洛硫酸酯酶α）等。退出市场的原因，除了患者数量有限，也于价格有关。百傲万里制药就称“尽管我们在过去几年中尽了最大努力，仍然没有促使唯铭赞进入医保报销体系，我们决定不再续签该产品的进口药品注册证。” 而罕见药进入医保，也不罕见。2022年国家医保药品目录调整，对罕见病用药开通单独申报渠道，支持其优先进入医保药品目录。截至目前，已有45种罕见病用药被纳入国家医保药品目录，覆盖26种罕见病。据国家医保局最新公告，2023年国家医保药品目录调整工作即将启动，明日（2023年7月1日）起开始申报。若盐酸沙丙蝶呤片能“药有所保”，一方面可以提高药物可及性，极大降低患者的负担，提高用药率；另一方面也能加快市场供给，减轻药企和经销商的销售压力。鲁南药业是否会进行盐酸沙丙蝶呤片的申报，又是否会顺利纳入医保？我们拭目以待。网参考资料: 1.药融云数据库 2.财经大健康：这款罕见病药即将退出中国市场，患者面临断药危机内容来源于网络，如有侵权，请联系删除。