Glycerol-Phenylbutyrate Treatment in Children With MCT Mutation (Allan-Herndon- Dudley Syndrome)

1. Introduction and rationale

Thyroid hormone (TH) is crucial for the development and metabolic state of virtually all tissues. TH signaling is regulated at the tissue level by intracellular conversion of the prohormone thyroxine (T4) to receptor-active 3,3',5-triiodothyronine (T3) or receptor-inactive 3,3',5'-triiodothyronine (rT3) by deiodinases. Since T3 receptors are located in the nucleus, TH transport across the plasma membrane is required for both TH metabolism and action. This process is facilitated by TH transporters, the most specific of which is monocarboxylate transporter 8 (MCT8) which is encoded by SLC16A2 gene located at chromosome X. MCT8 is critical for the transport of TH in a number of tissues, in particular the brain. Hemizygous mutations of MCT8 in males cause the Allan-Herndon-Dudley syndrome (AHDS), a severe neurodevelopmental disorder that is accompanied by abnormal TH levels.

The neurological phenotype is characterized by severe neurodevelopmental retardation starting at the first few month of life. Initially, AHDS patients also have peripheral hypotonia but this usually progresses to spastic quadriplegia. Brain MRI of AHDS patients shows delayed myelination.

The remarkable clinical spectrum of AHDS is probably derived from the defect in T3 entry in MCT8-expressing neurons and, thus, deprivation of TH in specific brain regions. The endocrine profile of patients with AHDS is characterized by moderately low T4, high T3 (usually more than twice the upper limit) and normal or mildly elevated TSH. The elevated serum T3 levels are toxic for peripheral tissues in which MCT8 is not important for TH transport, resulting in hyperthyroid symptoms such as low body weight, tachycardia, insomnia and muscle wasting. This peripheral phenotype is progressive with age.

Currently, no effective therapy is available for AHDS patients. Over the last decade, the main research efforts focused on thyromimetic agents that are not relied on MCT8 but might enter the central nervous system (CNS) neurons through alternative membrane transporters. Studies in Mct8 KO mice with the T3 analog 3,5-diiodothyropropionic acid (DITPA) demonstrated T3-like effects in the brain and a decrease in serum T3 levels, which attenuated the thyrotoxic state of peripheral tissues. It should be emphasized however that although mice model mimics the thyroid function profile typical to AHDS, it has normal neurological development. This study prompted a study in 4 AHDS patients. DITPA treatment normalized the elevated serum levels of T3 and TSH, while T4 and rT3 levels were increased to normal lower range. There was improvement neither in neurodevelopmental functions nor in peripheral phenotype of the patients. Following the limited effects of DITPA treatment, an alternative thyromimetic agent was suggested: tetraiodothyroacetic acid (Triac [Tiratricol,Téatrois]). In a report of multicenter international studies published in The lancet Diabetes and Endocrinology (2019), escalating dose schedule of Triac yielded reduced levels of T3 to the normal range and similar reduction in T4 and TSH. Yet, there no improvement of motor and cognitive skills was observed.