Division of Reproductive Endocrinology and Infertility, Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, Georgia, USA.
Adult Inherited Metabolic Diseases Department, Salford Royal Foundation NHS Trust, Salford, UK.
J Inherit Metab Dis. 2022 Nov;45(6):1106-1117. doi: 10.1002/jimd.12556. Epub 2022 Sep 26.
Patients with galactosemia who carry the S135L (c.404C > T) variant of galactose-1-P uridylyltransferase (GALT), documented to encode low-level residual GALT activity, have been under-represented in most prior studies of outcomes in Type 1 galactosemia. What is known about the acute and long-term outcomes of these patients, therefore, is based on very limited data. Here, we present a study comparing acute and long-term outcomes of 12 patients homozygous for S135L, 25 patients compound heterozygous for S135L, and 105 patients homozygous for two GALT-null (G) alleles. This is the largest cohort of S135L patients characterized to date. Acute disease following milk exposure in the newborn period was common among patients in all 3 comparison groups in our study, as were long-term complications in the domains of speech, cognition, and motor outcomes. In contrast, while at least 80% of both GALT-null and S135L compound heterozygous girls and women showed evidence of an adverse ovarian outcome, prevalence was only 25% among S135L homozygotes. Further, all young women in this study with even one copy of S135L achieved spontaneous menarche; this is true for only about 33% of women with classic galactosemia. Overall, we observed that while most long-term outcomes trended milder among groups of patients with even one copy of S135L, many individual patients, either homozygous or compound heterozygous for S135L, nonetheless experienced long-term outcomes that were not mild. This was true despite detection by newborn screening and both early and life-long dietary restriction of galactose. This information should empower more evidence-based counseling for galactosemia patients with S135L.
患有半乳糖血症的患者，如果携带半乳糖-1-磷酸尿苷酰转移酶（GALT）的 S135L（c.404C>T）变异，该变异已被证明编码低水平残留 GALT 活性，在大多数关于 1 型半乳糖血症患者结局的先前研究中代表性不足。因此，关于这些患者的急性和长期结局的了解是基于非常有限的数据。在这里，我们比较了 12 名纯合 S135L 患者、25 名复合杂合 S135L 患者和 105 名纯合 GALT 缺失（G）等位基因的患者的急性和长期结局。这是迄今为止对 S135L 患者进行的最大规模的队列研究。在我们的研究中，所有 3 个比较组的新生儿期暴露于牛奶后的急性疾病都很常见，言语、认知和运动结局的长期并发症也很常见。相比之下，虽然 GALT 缺失和 S135L 复合杂合子的女孩和女性中至少有 80%表现出不良卵巢结局的证据，但在 S135L 纯合子中仅为 25%。此外，在这项研究中，所有携带 S135L 一个拷贝的年轻女性都出现了自发性初潮；而在经典半乳糖血症女性中，只有约 33%的女性如此。总的来说，我们观察到，虽然在携带 S135L 一个拷贝的患者中，大多数长期结局的严重程度趋势较为温和，但仍有许多患者（无论是纯合子还是复合杂合子）的长期结局并不温和。尽管新生儿筛查、早期和终生限制半乳糖饮食都能检测到 S135L，但仍存在这种情况。这些信息应该为 S135L 半乳糖血症患者提供更具循证的咨询。
