From neuroanatomy to mechanisms of disability and treatment

Abstract

Mechanisms underlying motor dysfunctions in Allan Herndon Dudley Syndrome remain largely unknown. Neuroanatomical studies performed in postmortem human brain tissue obtained from control versus MCT8-deficient patients provide a suitable strategy to further understand underlying alterations of motor system circuitries. Our recent findings indicate that normal MCT8 expression is tightly regulated, both spatially and temporally, during development of the normal motor system. Particularly, MCT8 expression increases in white matter tracts during myelination. We have also found that the motor system of MCT8 deficient brains is affected of combined gray and white matter abnormalities that can be found either in prenatal and postnatal stages, and that reveal the impairment of several key developmental processes such as neuronal differentiation, myelination and synaptogenesis. Our observations in motor cortices, cerebellum and main motor descending tracts confirm the importance of the modulation of thyroid hormones availability during motor system ontogeny. These results try to outline the intervening driver molecular processes that lead this rare disease in order to support the refining of current therapeutic approaches and to pursue therapeutic targets in the future. Our results also point to the relevance of persevering on translational research towards plausible prenatal diagnosis and treatment for these patients.