Amnon Zung, Theo J Visser, Andre´ G Uitterlinden, Fernando Rivadeneira and Edith C H Friesema

Abstract: 

Objective: The monocarboxylate transporter 8 (MCT8; SLC16A2) has a pivotal role in neuronal triiodothyronine (T3) 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 T3 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 (LT4) or liothyronine (LT3) treatment intending to overcome the T3 uptake resistance through alternative transporters.

Methods: 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 LT4 treatment and two periods (3 months each) of low- and high-dose LT3 were evaluated.

Results: 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 T3 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.

Conclusion: We identified a 70 kb deletion encompassing exons 2–6 of the MCT8 gene in our AHDS patient. Both LT4 and LT3 administration had no therapeutic effect. Alternatively, treatment of AHDS patients with thyroid hormone analogs should be considered.