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

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Rationale: Thyroid hormone (TH) is crucial for normal brain development. The transporter monocarboxlate transporter 8 (MCT8), located at various organs including brain neurons, is crucial for cellular transport of TH, mainly T3 . A defect in this transporter causes Allan-Herndon-Dudley syndrome (AHDS), which characterized by severe motor and cognitive retardation. Serum TH tests typically show low T4, high T3 and mildly elevated TSH. The neurological phenotype entails diminished TH transport into the brain. On the other hand, elevated serum T3 leads to hypermetabolic status in peripheral tissues. Subsequently, AHDS patients have a low body weight and muscle mass. Currently, no effective treatment is available. Over the last decade, several studies focused on the effect of T3 analogues, that their trans-membrane transport is not mediated by MCT8. Two analogues were studied: Diiodothyropropionic acid (DITPA) and tetraiodothyroacetic acid (Triac). Both agents have demonstrated improvement in serum TH levels (mainly T3 and TSH) but no change in the neurocognitive status of the patients. Recently, several studies have demonstrated that sodium phenylbutyrate (PB) acting as a chaperon and increase the expression of MCT8 in the cell membrane. Subsequently, cells transfected with various mutations in MCT8 have shown remarkable improvement in T3 transport into the cytoplasm. We hypothesize that treatment of AHDS patients with glycerol phenylbutyrate (GPB) will improve thyroid function and neurodevelopmental parameters and relieve symptoms resulting from toxic T3 levels in peripheral tissues. Objective: To test safety and efficacy of PB treatment in AHDS patients. Primary objectives: To determine the effect of PB treatment on serum levels of TH. Secondary objective: 1. To determine the effect of PB on T3-associated hyperthyroid state in peripheral tissues. 2. To determine the effects of PB treatment on the neurodevelopmental status. Study design: therapeutic prospective trial. Study population: Up to 6 AHDS patients with genetically proven ADHD. Intervention: all participants will receive an escalating dose of PB in the form of Glycerol-PB (commercial name Ravicti) until individual serum T3 levels have been normalized or dose limiting toxicities occur. Duration of treatment: 12 months including the wash-out period of 1 month from the current Triac therapy

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