Heterogeneous clinical characteristics of Allan-Herndondudley syndrome with SLC16A2 mutations

Purpose: The purpose of this study was to expand our understanding of phenotypic and genetic variation in Allan-Herndon-Dudley syndrome (AHDS), which is a rare X-linked mental retardation syndrome characterized by hypotonia, generalized spasticity, and moderate-to-severe psychomotor retardation. AHDS is caused by a mutation of solute carrier family 16 member 2 (SLC16A2), which encodes monocarboxylate transporter 8 (MCT8), a transporter of triiodothyronine (T₃) into neurons. Methods: We enrolled nine patients with AHDS from unrelated families, except for two patients who were cousins, through a retrospective chart review. Clinical features, brain imaging, electroencephalograms, thyroid hormone profiles, and genetic data were reviewed retrospectively and compared with previously reported cases. Results: We found three novel and five previously reported pathogenic variants in nine patients from eight families. All patients presented with hypotonia, spasticity, severe developmental delay, and elevated serum T₃ levels. Cataplexy, which is a previously unreported phenotype, was found in two patients with the same mutation. In our cohort, seizures were uncommon (n=1) but intractable. Conclusion: This study broadens the known phenotypic variations of AHDS, ranging from relatively mild global developmental delay to a severe form of encephalopathy with hypotonia, spasticity, and no acquisition of independent sitting. The syndromic classification or genetic etiology of global developmental delay is extremely heterogeneous; therefore, early clinical suspicion is challenging for clinicians. However, severe mental retardation with hypotonia, spasticity, and elevated serum T₃ levels in boys is a highly suspicious clinical clue for the early diagnosis of AHDS.