MCT8 deficiency in females

CONTEXT: Monocarboxylate transporter (MCT) 8 facilitates thyroid hormone transport across the blood-brain-barrier. Pathogenic variants in SLC16A2 cause MCT8 deficiency (Allan-Herndon-Dudley syndrome), characterized by intellectual and motor disability and abnormal thyroid function tests. MCT8 deficiency typically affects males due to its X-linked inheritance. Here, we report 8 female patients with heterozygous pathogenic variants in SLC16A2 who presented with variable neurocognitive impairment, behavioural problems and thyroid hormone function abnormalities. METHODS: We performed X-chromosome inactivation studies in female patients in whom heterozygous pathogenic variants in SLC16A2 were identified. The impact of SLC16A2 variants on thyroid hormone transport was assessed in transfected cells and patient-derived fibroblasts. RESULTS: In all patients (mean age 8.6 years, range 2.3-25 years) routine care genetic analyses identified heterozygous variants in SLC16A2 (p.(R445C), p.(N193I), p.(G276R), t(X;20) resulting in a breakpoint in intron 1, t(X;19) resulting in a breakpoint in SLC16A2, p.(I562Sfs566*), p.(G221R)). All missense variants showed substantially reduced MCT8-mediated thyroid hormone uptake in transiently transfected cells. X-chromosome inactivation studies in patient cells showed skewed X-inactivation in all 7 evaluated individuals. In 5 out of 7 evaluated cases, MCT8-mediated T3 uptake in patient-derived fibroblasts was impaired to a similar degree as in fibroblasts derived from male patients with MCT8 deficiency. CONCLUSIONS: Female patients with heterozygous pathogenic variants in SLC16A2 and skewed X-chromosome inactivation may present variable neuro(psycho)logical, behavioural and thyroid function test abnormalities. Female patients presenting with neurocognitive impairment and abnormal thyroid hormone function tests (low free T4 and/or high total T3 concentrations) should be tested for genetic variants in SLC16A2.