The basal ganglia: a new possible therapeutic target in the Allan-Herndon-Dudley Syndrome

Resumen del póster presentado al 3rd Symposium on Biomedical Research: "Advances and Perspectives in Neuroscience", celebrado en la Universidad Autónoma de Madrid el 22 de abril de 2016.The Allan-Herndon-Dudley syndrome (AHDS) is a rare disease caused by mutations in the gene SLC16A2, which codifies for the monocarboxylate transporter 8 (MCT8), the solely cell-membrane transporter that specifically transports thyroid hormones. The altered expression of the mutated MCT8 causes peripheral hyperthyroidism and brain hypothyroidism, which is thought to be the cause of the neurological phenotype in AHDS patients that includes mental and developmental retardation, hypotonia and in most of the cases epilepsy. These clinical features start early in the infancy and develop in the adulthood to spastic tetraplegia and paroxysmal dyskinesia. The mechanisms underlying the disease are unknown so far and there is not an effective treatment. In this study, we have focused our work on the basal ganglia, as they are part of the motor voluntary movement controlling system. We have analyzed human paraffin-embedded brain sections of the basal ganglia taken from necropsies of AHDS patients and controls by immunohistochemistry for detection of MCT8, some of the characteristic markers of striatal neural populations (enkephalin and choline acetyltransferase) and other markers of synapsis (synaptophysin) or damage. We have observed an alteration of the basal ganglia circuitry based on the abnormal expression pattern of enkephalin and choline acetyltransferase in the striatum of the AHDS patients. We have also observed alterations in the synaptophysin staining in patients versus control basal ganglia. These results indicate that the basal ganglia are severely affected by mutations in MCT8 and that structural and functional alterations in this region could be the cause of some clinical features found in AHDS patients, which suggests that those areas could be considered therapeutic targets in AHDS.Supported by grants from the Spanish Ministry of Economy and Competitiveness (MINECO) SAF2014-54919-R.Peer Reviewe

The basal ganglia: a new possible therapeutic target in MCT8 deficiency

Resumen del trabajo presentado al MCT8 Symposium, celebrado en Los Angeles (California-USA) del 4 al 6 de enero de 2017.The Allan-Herndon-Dudley syndrome is a rare disease caused by mutations in the gene SLC16A2, which codifies for the specific thyroid hormone cell-membrane transporter monocarboxylate transporter 8 (MCT8). The altered expression of MCT8 leads to a singular scenario of prenatal brain hypothyroidism that is thought to underlie a dramatic neurological postnatal phenotype of developmental retardation, hypotonia and epilepsy. These clinical features start in the early infancy. Spastic tetraplegia, intellectual disability and paroxysmal dyskinesias appear posteriorly. The mechanisms underlying these clinical manifestations are poorly understood and, subsequently, a rational basis for a targeted, symptomatic therapy is still lacking. The severe impairment in motor control of these patients, as well as the learning problems, points to basal ganglia dysfunction. Thus, we have analyzed human paraffin-embedded brain sections taken from necropsies of MCT8-deficient and control patients and we have immunohistochemically stained them to detect the MCT8 transporter, structural cell and synaptic proteins and a series of striatal markers. Our results provide neuroanatomical evidence for severe structural and neurochemical deficiencies that might well explain the poor regulatory control of excitatory-inhibitory balance in basal ganglia microcircuitry and the extrapyramidal signs in patients affected by MCT8 mutations. This study, and others with more cases, could be the conceptual basis for further studies with ‘in vivo’ non-invasive neuroimaging techniques to facilitate a rational improvement of the current symptomatic drug therapies for this disease.Peer Reviewe