Pediatric Endocrinology Unit, Kaplan Medical Center, Affiliated with the Hebrew University of Jerusalem, Rehovot 76100, Israel Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
Eur J Endocrinol. 2011 Nov;165(5):823-30. doi: 10.1530/EJE-11-0358. Epub 2011 Sep 6.
The monocarboxylate transporter 8 (MCT8; SLC16A2) has a pivotal role in neuronal triiodothyronine (T(3)) uptake. Mutations of this transporter determine a distinct X-linked psychomotor retardation syndrome (Allan-Herndon-Dudley syndrome (AHDS)) that is attributed to disturbed thyroid hormone levels, especially elevated T(3) levels. We describe the genetic analysis of the MCT8 gene in a patient suspected for AHDS and the clinical and endocrine effects of L-thyroxine (LT(4)) or liothyronine (LT(3)) treatment intending to overcome the T(3) uptake resistance through alternative transporters.
The six exons of the MCT8 gene were amplified individually by PCR. As multiple exons were missing, the length of the X-chromosomal deletion was determined by a dense SNP array, followed by PCR-based fine mapping to define the exact borders of the deleted segment. The clinical and endocrine data of the patient during 6.5 years of LT(4) treatment and two periods (3 months each) of low- and high-dose LT(3) were evaluated.
A partial deletion of the MCT8 gene (comprising five of six exons) was detected, confirming the suspected AHDS. MCT8 dysfunction was associated with partial resistance to T(3) at the hypothalamus and pituitary level, with normal responsiveness at the peripheral organs (liver and cardiovascular system). Thyroid hormone administration had no beneficial effect on the neurological status of the patient.
We identified a 70 kb deletion encompassing exons 2-6 of the MCT8 gene in our AHDS patient. Both LT(4) and LT(3) administration had no therapeutic effect. Alternatively, treatment of AHDS patients with thyroid hormone analogs should be considered.
单羧酸转运蛋白 8（MCT8；SLC16A2）在神经元摄取三碘甲状腺原氨酸（T（3））中起着关键作用。这种转运蛋白的突变决定了一种独特的 X 连锁精神运动发育迟缓综合征（Allan-Herndon-Dudley 综合征（AHDS）），这归因于甲状腺激素水平紊乱，特别是 T（3）水平升高。我们描述了疑似 AHDS 患者 MCT8 基因突变的遗传分析，以及左甲状腺素（LT（4））或三碘甲状腺原氨酸（LT（3））治疗的临床和内分泌影响，旨在通过替代转运体克服 T（3）摄取抵抗。
通过 PCR 单独扩增 MCT8 基因的六个外显子。由于多个外显子缺失，通过密集的 SNP 阵列确定 X 染色体缺失的长度，然后通过基于 PCR 的精细作图来确定缺失片段的精确边界。评估了患者在 LT（4）治疗 6.5 年期间和两个时期（每个时期 3 个月）的 LT（3）低剂量和高剂量期间的临床和内分泌数据。
检测到 MCT8 基因的部分缺失（包括六个外显子中的五个），证实了疑似 AHDS。MCT8 功能障碍与下丘脑和垂体水平对 T（3）的部分抵抗有关，而外周器官（肝脏和心血管系统）对 T（3）的反应正常。甲状腺激素给药对患者的神经状态没有有益影响。
我们在 AHDS 患者中鉴定出包含 MCT8 基因外显子 2-6 的 70kb 缺失。LT（4）和 LT（3）给药均无治疗效果。或者，应考虑用甲状腺激素类似物治疗 AHDS 患者。
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