Background

Classical Galactosemia (CG) is an inherited disorder of galactose metabolism caused by a deficiency of the galactose-1-phosphate uridylyltransferase (GALT) enzyme resulting in neurocognitive complications. As in many Inborn Errors of Metabolism, the metabolic pathway of CG is well-defined, but the pathophysiology and high variability in clinical outcome are poorly understood. The aim of this study was to investigate structural changes of the brain of CG patients on MRI and their association with clinical outcome.

Methods

In this prospective cohort study an MRI protocol was developed to evaluate gray matter (GM) and white matter (WM) volume of the cerebrum and cerebellum, WM hyperintensity volume, WM microstructure and myelin content with the use of conventional MRI techniques, diffusion tensor imaging (DTI) and quantitative T1 mapping. The association between several neuroimaging parameters and both neurological and intellectual outcome was investigated.

Results

Twenty-one patients with CG (median age 22 years, range 8–47) and 24 controls (median age 30, range 16–52) were included. Compared to controls, the WM of CG patients was lower in volume and the microstructure of WM was impaired both in the whole brain and corticospinal tract (CST) and the lower R1 values of WM, GM and the CST were indicative of less myelin. The volume of WM lesions were comparable between patients and controls. The 9/16 patients with a poor neurological outcome (defined as the presence of a tremor and/or dystonia), demonstrated a lower WM volume, an impaired WM microstructure and lower R1 values of the WM indicative of less myelin content compared to 7/16 patients without movement disorders. In 15/21 patients with a poor intellectual outcome (defined as an IQ < 85) both GM and WM were affected with a lower cerebral and cerebellar WM and GM volume compared to 6/21 patients with an IQ ≥ 85. Both the severity of the tremor (as indicated by the Tremor Rating Scale) and IQ (as continuous measure) were associated with several neuroimaging parameters such as GM volume, WM volume, CSF volume, WM microstructure parameters and R1 values of GM and WM.

Conclusion

In this explorative study performed in patients with Classical Galactosemia, not only WM but also GM pathology was found, with more severe brain abnormalities on MRI in patients with a poor neurological and intellectual outcome. The finding that structural changes of the brain were associated with the severity of long-term complications indicates that quantitative MRI techniques could be of use to explain neurological and cognitive dysfunction as part of the disease spectrum. Based on the clinical outcome of patients, the absence of widespread WM lesions and the finding that both GM and WM are affected, CG could be primarily a GM disease with secondary damage to the WM as a result of neuronal degeneration. To investigate this further the course of GM and WM should be evaluated in longitudinal research, which could also clarify if CG is a neurodegenerative disease.

中文翻译：

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灰质和白质均受经典半乳糖血症的影响：神经影像学与临床结局之间关系的探索性研究

背景

古典半乳糖血症（CG）是一种半乳糖代谢的遗传性疾病，由半乳糖-1-磷酸尿嘧啶转移酶（GALT）酶的缺乏引起，导致神经认知并发症。如同许多先天性代谢错误一样，CG的代谢途径已被明确定义，但对临床结果的病理生理学和高度变异性知之甚少。这项研究的目的是调查MRI患者CG的大脑结构变化及其与临床结局的关系。

方法

在这项前瞻性队列研究中，开发了一种MRI协议，以通过使用常规MRI技术，扩散张量成像来评估大脑和小脑的灰质（GM）和白质（WM）体积，WM高强度体积，WM显微结构和髓磷脂含量（DTI）和定量T1映射。研究了几个神经影像学参数与神经和智力结果之间的关联。

结果

包括二十一名CG患者（中位年龄22岁，范围8-47）和24名对照（中位年龄30岁，范围16-52）。与对照组相比，CG患者的WM体积较小，并且在全脑和皮质脊髓束（CST）中WM的微观结构均受到损害，并且WM，GM和CST的R1值较低表明髓鞘较少。患者和对照组之间的WM病变体积相当。9/16例神经系统疾病预后不良（定义为存在震颤和/或肌张力障碍）的患者表现出较低的WM体积，受损的WM显微结构和较低的WM R1值，表明髓磷脂含量低于7 / 16例无运动障碍。在15/21例智力低下的患者中（智商<

结论

在这项针对经典半乳糖血症患者的探索性研究中，不仅发现了WM，而且还发现了GM病理，对于神经系统和智力结果较差的患者，MRI上的脑部异常更为严重。大脑结构的变化与长期并发症的严重程度相关的发现表明，定量MRI技术可用于解释神经系统和认知功能障碍，并将其作为疾病谱的一部分。根据患者的临床结果，不存在广泛的WM病变以及发现GM和WM均受影响的发现，CG可能主要是由于神经元变性而导致WM继发性损伤的GM疾病。为了对此进行进一步调查，应在纵向研究中评估GM和WM的过程，