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

IF 2.6 4区医学 Q2 CLINICAL NEUROLOGY Movement Disorders Clinical Practice Pub Date : 2024-07-12 DOI:10.1002/mdc3.14157

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

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Abstract

Background: The 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.

Objectives: The aim was to study 4 new cases of arGTPCH deficiency and systematically review patients reported in the literature.

Methods: Clinical, biochemical, and genetic data and treatment response of 45 patients are presented.

Results: Three 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.

Conclusions: The 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.

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常染色体隐性三磷酸鸟苷环化酶 I 缺乏症：重新定义表型谱和结果。

背景：GCH1 基因编码鸟苷三磷酸环氢酶 I (GTPCH)，该酶催化四氢生物蝶呤 (BH4) 生物合成过程中的限速步骤，BH4 是产生单胺神经递质的关键辅助因子。常染色体显性 GTPCH（adGTPCH）缺乏症是多巴反应性肌张力障碍（DRD）最常见的病因，而隐性 GTPCH（arGTPCH）缺乏症则是一种极罕见且特征不清的疾病，表现更早、更复杂，可能会扰乱神经发育过程。在此，我们描述了 ARGTPCHD 的表型谱，并研究了生化和遗传相关因素对疾病结果的预测价值：目的：研究 4 例 arGTPCH 缺乏症新病例，并系统回顾文献中报道的患者：方法：介绍45例患者的临床、生化和遗传数据以及治疗反应：结果：概述了三种表型：(1) 伴有深度残疾的早幼粒细胞脑病表型（45 例患者中的 24 例），(2) 在运动障碍出现前发育停滞/退化的婴幼儿期发病的肌张力障碍-帕金森病表型（45 例患者中的 7 例），以及 (3) 迟发的 DRD 表型（45 例患者中的 14 例）。这三种表型对药物治疗均有反应，前两种表型必须尽早开始药物治疗，以防止出现致残性神经发育后果。BH4缺陷和遗传变异严重程度的梯度是这3个临床亚组的特征。在第二和第三组中未观察到高苯丙氨酸血症，但与智力残疾的可能性较高有关：结论：arGTPCH 缺乏症的临床表现是一个从早发性脑病到典型 DRD 的连续过程。基因型和生化改变可帮助早期诊断并预测临床严重程度。早期治疗仍然至关重要，尤其是对最严重的患者。

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来源期刊

Movement Disorders Clinical Practice CLINICAL NEUROLOGY-

CiteScore

4.00

自引率

7.50%

发文量

218

期刊介绍： Movement Disorders Clinical Practice- is an online-only journal committed to publishing high quality peer reviewed articles related to clinical aspects of movement disorders which broadly include phenomenology (interesting case/case series/rarities), investigative (for e.g- genetics, imaging), translational (phenotype-genotype or other) and treatment aspects (clinical guidelines, diagnostic and treatment algorithms)

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