Português

Abstract

Introduction: Allan-Herndon-Dudley Syndrome (AHDS) is a rare and devastating X-linked genetic encephalopathy caused by mutations in the SLC16A2 gene, which encodes the monocarboxylate transporter 8 (MCT8). Functional deficiency of MCT8 impairs the proper transport of triiodothyronine (T3) into the central nervous system, resulting in functional cerebral hypothyroidism and peripheral thyrotoxicosis. This hormonal imbalance severely compromises neuropsychomotor development, leading to profound motor delay, movement disorders, seizures, systemic metabolic disturbances, and multisystem involvement. Objective: To critically review recent advances in the understanding of the molecular pathophysiology, clinical manifestations, diagnostic methods, and emerging therapeutic strategies for AHDS, with emphasis on the importance of early diagnosis, targeted intervention, and the development of guidelines for public health policies. Methods: A comprehensive literature review was conducted on publications from 2010 to 2024, using systematic searches in the PubMed, UpToDate, GeneReviews, Orphanet, Rare Disease Observatory of the University of São Paulo (USP), and official documents from the European Medicines Agency (EMA). Eligible sources included observational clinical studies, controlled clinical trials, systematic reviews, international guidelines, and high-quality narrative reviews. Inclusion criteria encompassed publications addressing genetic, pathophysiological, clinical, and therapeutic aspects of AHDS. Isolated case reports, clinical series with fewer than three patients, non-peer-reviewed articles, and pre-print publications were excluded. Results: MCT8 deficiency disrupts myelination, neuronal differentiation, and the development of synaptic networks in the central nervous system, while simultaneously inducing peripheral thyrotoxicosis. The characteristic hormonal profile (elevated free T3, reduced free T4, and normal or slightly elevated TSH) combined with the identification of pathogenic mutations in SLC16A2 is essential for diagnosis. Triac (triiodothyroacetic acid) has emerged as the first approved therapy to reduce peripheral thyrotoxicosis in AHDS patients. New therapeutic approaches, including the use of sobetirome and gene therapy strategies employing AAV9 vectors, show promising perspectives. However, challenges persist, such as diagnostic delays, inequalities in therapy access, and the absence of systematic neonatal screening programs. Conclusion: The implementation of neonatal screening strategies, the expansion of access to emerging therapies, and the strengthening of genetic counseling services are crucial to improving AHDS prognosis. Ongoing investments in translational research, multicenter patient registries, and the development of inclusive public health policies are imperative to ensure the democratization of scientific advances and to improve the quality of life for individuals affected by the disease.