Child Neurology and Psychiatry Unit, Department of Human Neurosciences, Sapienza University of Rome, Rome, Italy.
Clinical Pathology Unit, Department of Experimental Medicine, AOU Policlinico Umberto I-Sapienza University, Rome, Italy.
Mov Disord Clin Pract. 2024 Sep;11(9):1072-1084. doi: 10.1002/mdc3.14157. Epub 2024 Jul 12.
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.
The aim was to study 4 new cases of arGTPCH deficiency and systematically review patients reported in the literature.
Clinical, biochemical, and genetic data and treatment response of 45 patients are presented.
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.
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.
GCH1 基因编码鸟苷三磷酸环化水解酶 I（GTPCH），该酶催化四氢生物蝶呤（BH4）生物合成的限速步骤，BH4 是单胺神经递质产生的关键辅因子。常染色体显性 GTPCH（adGTPCH）缺乏症是多巴反应性肌张力障碍（DRD）最常见的原因，而隐性形式（arGTPCH）是一种极为罕见且特征描述不完善的疾病，具有更早和更复杂的表现，可能会破坏神经发育过程。在这里，我们描绘了 ARGTPCHD 的表型谱，并研究了生化和遗传相关性对疾病结果的预测价值。
研究 4 例新的 arGTPCH 缺乏症病例，并对文献中报道的患者进行系统综述。
呈现了 45 例患者的临床、生化和遗传数据以及治疗反应。
概述了 3 种表型：（1）早发性婴儿脑病伴严重残疾（45 例患者中的 24 例），（2）伴婴儿/幼儿期起病的肌张力障碍-帕金森病表型，运动障碍出现之前出现发育停滞/倒退（45 例患者中的 7 例），和（3）迟发性 DRD 表型（45 例患者中的 14 例）。所有 3 种表型对药物治疗均有反应，前两种表型必须及早开始治疗，以防止致残性神经发育结局。BH4 缺陷和遗传变异严重程度的梯度特征可将这 3 个临床亚组区分开来。第 2 和第 3 组未观察到高苯丙氨酸血症，且与智力障碍的可能性更高相关。
arGTPCH 缺乏症的临床谱是从早发性脑病到经典 DRD 的连续谱。基因型和生化改变可实现早期诊断，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。
