Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.
Emory College of Arts and Sciences, Emory University, Atlanta, GA, USA.
Mol Genet Metab. 2023 Nov;140(3):107708. doi: 10.1016/j.ymgme.2023.107708. Epub 2023 Oct 11.
Classic galactosemia (CG) is a potentially lethal genetic disorder that results from profound deficiency of galactose-1-P uridylyltransferase. Despite early detection and life-long dietary restriction of galactose, which is the current standard of care, many patients with CG grow to experience a range of long-term developmental complications that can include difficulties with speech/voice/language, cognitive, motor, and psychosocial outcomes, among other problems. That these complications are common in CG is well-documented, but whether they are also progressive has been a point of controversy for decades. Here, we addressed the question of whether long-term outcomes in CG are progressive by analyzing a robust data set in each of 4 ways. First, we compared cross-sectional Vineland-3 Adaptive Behavior Scales scores for 101 cases and 65 unaffected sibling controls and found no evidence of consistently declining scores with age. Second, we analyzed longitudinal Vineland-3 subdomain scores for 45 cases and 34 controls to see if individual participants demonstrated developmental gains (positive slope) or losses (negative slope) over time. The changes in most growth scale value (GSV) scores, which are not normed, were positive for both cases and controls <10y, and either positive or near zero for participants ≥10y. In contrast, the slopes of most v-Scale scores, which are normed, were negative for many cases <10y, indicating that these children, while gaining milestones, were gaining them at a slower pace than their counterparts in the reference population. Third, we analyzed medical records from 76 cases, assigning ordinal scores for complications and gathering the quantitative results of relevant formal assessments where available. Both cross-sectional and longitudinal analyses of both ordinal and formal assessment scores confirmed that outcomes were mostly stable, albeit with some ups and downs in isolated cases. Finally, we analyzed data collected via custom family-response surveys from 124 cases and 67 controls regarding each participant's perceived symptom severity over time. Among cases, the percentages of respondents reporting worsening symptoms over time for speech, cognitive, motor, and psychosocial outcomes were 0.8%, 6.6%, 5.2%, and 9.8%, respectively. Among controls, the corresponding percentages were 0.0%, 1.5%, 1.5%, and 6.5%, respectively. These results provide compelling evidence that long-term developmental complications are not progressive for a majority of patients with CG.
经典型半乳糖血症 (CG) 是一种潜在致命的遗传疾病，由半乳糖-1-磷酸尿苷酰转移酶的严重缺乏引起。尽管目前的标准治疗方法是早期发现和终生限制半乳糖的摄入，但许多 CG 患者仍会经历一系列长期的发育并发症，包括言语/语音/语言、认知、运动和社会心理等方面的困难。这些并发症在 CG 中很常见，这一点已经有充分的记录，但几十年来，它们是否也在进展一直是一个争议点。在这里，我们通过以下 4 种方式分析了一个强大的数据集，以解决 CG 患者的长期预后是否是进展性的问题。首先，我们比较了 101 例病例和 65 例无相关同胞对照组的 Vineland-3 适应行为量表的横断面得分，没有发现得分随年龄持续下降的证据。其次，我们分析了 45 例病例和 34 例对照组的纵向 Vineland-3 亚域得分，以观察个体参与者是否随着时间的推移表现出发育上的增益（正斜率）或损失（负斜率）。对于大多数生长量表值（GSV）得分，由于未进行标准化，因此对于病例和对照组中年龄<10 岁的患者来说，变化均为正值，而对于年龄≥10 岁的患者来说，变化则为正值或接近零。相比之下，对于许多年龄<10 岁的病例，大多数 v-量表得分的斜率为负值，这表明这些儿童虽然在获得里程碑，但比参考人群中的同龄人获得的速度要慢。第三，我们分析了 76 例病例的医疗记录，为并发症分配了序数评分，并收集了可用的相关正式评估的定量结果。对序数和正式评估得分的横断面和纵向分析都证实，结果大多是稳定的，尽管在个别病例中存在一些起伏。最后，我们分析了 124 例病例和 67 例对照组通过定制的家庭反应调查收集的数据，了解每个参与者随时间推移的感知症状严重程度。在病例中，报告随时间推移言语、认知、运动和社会心理结局症状恶化的受访者比例分别为 0.8%、6.6%、5.2%和 9.8%。在对照组中，相应的百分比分别为 0.0%、1.5%、1.5%和 6.5%。这些结果提供了令人信服的证据，表明对于大多数 CG 患者来说，长期发育并发症不是进展性的。
