Bisello Giovanni, Saris Christiaan G J, Franchini Rossella, Verbeek Marcel M, Willemsen Michel A A P, Perduca Massimiliano, Bertoldi Mariarita
Department of Neuroscience, Biomedicine and Movement Sciences, Section of Biochemistry, University of Verona, Strada Le Grazie 8, 37134 Verona, Italy.
Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Geert Grooteplein 10, 6525 GA Nijmegen, the Netherlands.
Mol Genet Metab Rep. 2024 Mar 16;39:101071. doi: 10.1016/j.ymgmr.2024.101071. eCollection 2024 Jun.
A case of an adult with borderline AADC deficiency symptoms is presented here. Genetic analysis revealed that the patient carries two AADC variants (NM_000790.3: c.1040G > A and c.679G > C) in compound heterozygosis, resulting in p.Arg347Gln and p.Glu227Gln amino acid alterations. While p.Arg347Gln is a known pathogenic variant, p.Glu227Gln is unknown. Combining clinical features to bioinformatic and molecular characterization of the AADC protein population of the patient (p.Arg347Gln/p.Arg347Gln homodimer, p.Glu227Gln/p.Glu227Gln homodimer, and p.Glu227Gln/p.Arg347Gln heterodimer), we determined that: i) the p.Arg347Gln/p.Arg347Gln homodimer is inactive since the alteration affects a catalytically essential structural element at the active site, ii) the p.Glu227Gln/p.Glu227Gln homodimer is as active as the wild-type AADC since the alteration occurs at the surface and does not change the chemical nature of the amino acid, and iii) the p.Glu227Gln/p.Arg347Gln heterodimer has a catalytic efficiency 75% that of the wild-type since only one of the two active sites is compromised, thus demonstrating a positive complementation. By this approach, the molecular basis for the mild presentation of the disease is provided, and the experience made can also be useful for personalized therapeutic decisions in other mild AADC deficiency patients. Interestingly, in the last few years, many previously undiagnosed or misdiagnosed patients have been identified as mild cases of AADC deficiency, expanding the phenotype of this neurotransmitter disease.
本文介绍了一例具有边缘性芳香族氨基酸脱羧酶（AADC）缺乏症状的成年患者。基因分析显示，该患者为复合杂合子，携带两个AADC变体（NM_000790.3: c.1040G>A和c.679G>C），导致p.Arg347Gln和p.Glu227Gln氨基酸改变。虽然p.Arg347Gln是已知的致病变体，但p.Glu227Gln尚不清楚。结合临床特征以及对患者AADC蛋白群体（p.Arg347Gln/p.Arg347Gln同二聚体、p.Glu227Gln/p.Glu227Gln同二聚体和p.Glu227Gln/p.Arg347Gln异二聚体）的生物信息学和分子特征分析，我们确定：i）p.Arg347Gln/p.Arg347Gln同二聚体无活性，因为该改变影响了活性位点上催化必需的结构元件；ii）p.Glu227Gln/p.Glu227Gln同二聚体与野生型AADC活性相同，因为该改变发生在表面且不改变氨基酸的化学性质；iii）p.Glu227Gln/p.Arg347Gln异二聚体的催化效率为野生型的75%，因为两个活性位点中只有一个受损，从而显示出正向互补。通过这种方法，提供了该疾病轻度表现的分子基础，所获得的经验也有助于其他轻度AADC缺乏患者的个性化治疗决策。有趣的是，在过去几年中，许多先前未被诊断或误诊的患者被确定为轻度AADC缺乏病例，从而扩展了这种神经递质疾病的表型。
