Heterogeneous Clinical Characteristics of Allan-Herndon-Dudley 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), the 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 male patients is a highly suspicious clinical clue for the early diagnosis of AHDS.