Pediatric Endocrinology Unit, Kaplan Medical Center, Rehovot 76100, Israel.
Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 12000, Israel.
J Clin Endocrinol Metab. 2024 Sep 16;109(10):2589-2601. doi: 10.1210/clinem/dgae146.
Monocarboxylate transporter 8 (MCT8) deficiency is a rare genetic disease that leads to severe global developmental delay. MCT8 facilitates thyroid hormone (TH) transport across the cell membrane, and the serum TH profile is characterized by high T3 and low T4 levels. Recent studies have shown that the chemical chaperone sodium phenylbutyrate (NaPB) restored mutant MCT8 function and increased TH content in patient-derived induced pluripotent stem cells, making it a potential treatment for MCT8 deficiency.
We aimed to assess the efficacy and safety of glycerol phenylbutyrate (GPB) in MCT8 deficiency.
We treated 2 monozygotic twins aged 14.5 years with MCT8 deficiency due to P321L mutation with escalating doses of GPB over 13 months. We recorded TH, vital signs, anthropometric measurements, and neurocognitive functions. Resting metabolic rate (RMR) was measured by indirect calorimetry. Serum metabolites of GPB were monitored as a safety measure. In vitro effects of NaPB were evaluated in MDCK1 cells stably expressing the MCT8P321L mutation. The effects of GPB were compared to the effects of DITPA and TRIAC, thyromimetic medications that the patients had received in the past.
NaPB restored mutant MCT8 expression in MDCK1 cells and increased T3 transport into cells carrying the P321L mutation. GPB treatment reduced high T3 and increased low T4 levels. The patients showed a significant weight gain simultaneously with a reduction in RMR. Only minor neurocognitive improvement was observed, in hyperreflexia score and in cognitive functions. Serum metabolites did not exceed the toxic range, but elevated liver transaminases were observed.
In the first report of GPB treatment in MCT8 deficiency we found an improvement in TH profile and body mass index, with minor neurodevelopmental changes.
单羧酸转运蛋白 8（MCT8）缺乏症是一种罕见的遗传性疾病，可导致严重的全面发育迟缓。MCT8 促进甲状腺激素（TH）穿过细胞膜的转运，血清 TH 谱的特征是 T3 水平高，T4 水平低。最近的研究表明，化学伴侣物苯丁酸钠（NaPB）恢复了突变 MCT8 的功能，并增加了患者来源的诱导多能干细胞中的 TH 含量，使其成为 MCT8 缺乏症的潜在治疗方法。
评估甘油苯丁酸酯（GPB）在 MCT8 缺乏症中的疗效和安全性。
我们对 2 名患有 MCT8 缺乏症的同卵双胞胎（年龄为 14.5 岁）进行了治疗，这些患者因 P321L 突变导致 MCT8 缺乏症，使用 GPB 进行了 13 个月的递增剂量治疗。我们记录了 TH、生命体征、人体测量学测量和神经认知功能。通过间接测热法测量静息代谢率（RMR）。作为安全性措施，监测 GPB 的血清代谢产物。我们在稳定表达 MCT8P321L 突变的 MDCK1 细胞中评估了 NaPB 的体外作用。我们将 GPB 的作用与患者过去接受过的甲状腺刺激药物 DITPA 和 TRIAC 的作用进行了比较。
NaPB 恢复了 MDCK1 细胞中突变 MCT8 的表达，并增加了携带 P321L 突变的细胞中 T3 的转运。GPB 治疗降低了高 T3 并增加了低 T4 水平。患者同时出现体重增加和 RMR 降低。仅观察到轻微的神经认知改善，表现在高反射评分和认知功能上。血清代谢产物未超过毒性范围，但观察到肝转氨酶升高。
在 MCT8 缺乏症中使用 GPB 治疗的首次报告中，我们发现 TH 谱和体重指数有所改善，神经发育变化较小。
