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The Galactose Index measured in fibroblasts of GALT deficient patients distinguishes variant patients detected by newborn screening from patients with classical phenotypes.
Molecular Genetics and Metabolism ( IF 3.8 ) Pub Date : 2020-01-09 , DOI: 10.1016/j.ymgme.2020.01.002
Mendy M Welsink-Karssies 1 , Michel van Weeghel 2 , Carla E M Hollak 3 , Hyung L Elfrink 2 , Mirian C H Janssen 4 , Kent Lai 5 , Janneke G Langendonk 6 , Esmee Oussoren 7 , Jos P N Ruiter 8 , Eileen P Treacy 9 , Maaike de Vries 10 , Sacha Ferdinandusse 8 , Annet M Bosch 1
Affiliation  

BACKGROUND The high variability in clinical outcome of patients with Classical Galactosemia (CG) is poorly understood and underlines the importance of prognostic biomarkers, which are currently lacking. The aim of this study was to investigate if residual galactose metabolism capacity is associated with clinical and biochemical outcomes in CG patients with varying geno- and phenotypes. METHODS Galactose Metabolite Profiling (GMP) was used to determine residual galactose metabolism in fibroblasts of CG patients. The association between the galactose index (GI) defined as the ratio of the measured metabolites [U13C]Gal-1-P/ [13C6]UDP-galactose, and both intellectual and neurological outcome and galactose-1-phosphate (Gal-1-P) levels was investigated. RESULTS GMP was performed in fibroblasts of 28 patients and 3 control subjects. The GI of the classical phenotype patients (n = 22) was significantly higher than the GI of four variant patients detected by newborn screening (NBS) (p = .002), two homozygous p.Ser135Leu patients (p = .022) and three controls (p = .006). In the classical phenotype patients, 13/18 (72%) had a poor intellectual outcome (IQ < 85) and 6/12 (50%) had a movement disorder. All the NBS detected variant patients (n = 4) had a normal intellectual outcome (IQ ≥ 85) and none of them has a movement disorder. In the classical phenotype patients, there was no significant difference in GI between patients with a poor and normal clinical outcome. The NBS detected variant patients had significantly lower GI levels and thus higher residual galactose metabolism than patients with classical phenotypes. There was a clear correlation between Gal-1-P levels in erythrocytes and the GI (p = .001). CONCLUSIONS The GI was able to distinguish CG patients with varying geno- and phenotypes and correlated with Gal-1-P. The data of the NBS detected variant patients demonstrated that a higher residual galactose metabolism may result in a more favourable clinical outcome. Further research is needed to enable individual prognostication and treatment in all CG patients.

中文翻译:

在GALT缺乏症患者的成纤维细胞中测量的半乳糖指数将新生儿筛查发现的变异型患者与经典表型患者区分开来。

背景技术对经典半乳糖血症(CG)患者临床结果的高度变异性了解甚少,并强调了目前缺乏的预后生物标志物的重要性。这项研究的目的是调查具有不同基因型和表型的CG患者的残留半乳糖代谢能力是否与临床和生化结果相关。方法采用半乳糖代谢谱(GMP)测定CG患者成纤维细胞中残留的半乳糖代谢。半乳糖指数(GI)定义为测得的代谢物[U13C] Gal-1-P / [13C6] UDP-半乳糖与智力和神经系统结果以及半乳糖1-磷酸(Gal-1- P)水平进行了研究。结果GMP在28例患者和3例对照受试者的成纤维细胞中进行。经典表型患者的GI(n = 22)显着高于通过新生儿筛查(NBS)检测到的四名变异患者(p = .002),两名纯合的p.Ser135Leu患者(p = .022)和三名控制(p = .006)。在经典表型患者中,13/18(72%)的智力结果较差(IQ <85),6/12(50%)的患者有运动障碍。在NBS中检测到的所有变异患者(n = 4)的智力结局均正常(IQ≥85),并且均无运动障碍。在典型的表型患者中,临床结果较差和正常的患者之间的胃肠道无明显差异。NBS检测到的变异患者的GI水平明显低于具有典型表型的患者,因此其残留的半乳糖代谢水平更高。红细胞中的Gal-1-P水平与GI之间存在明显的相关性(p = .001)。结论GI能够区分具有不同基因型和表型并与Gal-1-P相关的CG患者。NBS检测到的变异患者的数据表明,较高的残留半乳糖代谢可能导致更有利的临床结果。需要进行进一步的研究以使所有CG患者能够进行单独的预后和治疗。
更新日期:2020-01-09
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