Project description:Thyroid hormone is essential for the proper development and function of the brain. The active form of thyroid hormone is T(3), which binds to nuclear receptors. Recently, a transporter specific for T(3), MCT8 (monocarboxylate transporter 8) was identified. MCT8 is highly expressed in liver and brain. The gene is located in Xq13 and mutations in MCT8 are responsible for an X-linked condition, Allan-Herndon-Dudley syndrome (AHDS). This syndrome is characterized by congenital hypotonia that progresses to spasticity with severe psychomotor delays. Affected males also present with muscle hypoplasia, generalized muscle weakness, and limited speech. Importantly, these patients have elevated serum levels of free T(3), low to below normal serum levels of free T(4), and levels of thyroid stimulating hormone that are within the normal range. This constellation of measurements of thyroid function enables quick screening for AHDS in males presenting with cognitive impairment, congenital hypotonia, and generalized muscle weakness.
Project description:Allan-Herndon-Dudley syndrome (AHDS) is an X-linked disorder caused by impaired thyroid hormone transporter. Patients with AHDS usually exhibit severe motor developmental delay, delayed myelination of the brain white matter, and elevated T3 levels in thyroid tests. Neurological examination of two patients with neurodevelopmental delay revealed generalized hypotonia, and not paresis, as the main neurological finding. Nystagmus and dyskinesia were not observed. Brain magnetic resonance imaging demonstrated delayed myelination in early childhood in both patients. Nevertheless, matured myelination was observed at 6 years of age in one patient. Although the key finding for AHDS is elevated free T3, one of the patients showed a normal T3 level in childhood, misleading the diagnosis of AHDS. Genetic analysis revealed two novel SLC16A2 mutations, p.(Gly122Val) and p.(Gly221Ser), confirming the AHDS diagnosis. These results indicate that AHDS diagnosis is sometimes challenging owing to clinical variability among patients.
Project description:Why do members of some species live in groups while others are solitary? Group living (sociality) has often been studied from an evolutionary perspective, but less is known about the neurobiology of affiliation outside the realms of mating and parenting. Colonial species offer a valuable opportunity to study nonsexual affiliative behavior between adult peers. Meadow voles (Microtus pennsylvanicus) display environmentally induced variation in social behavior, maintaining exclusive territories in summer months, but living in social groups in winter. Research on peer relationships in female meadow voles demonstrates that these selective preferences are mediated differently than mate relationships in socially monogamous prairie voles, but are also impacted by oxytocin and HPA axis signaling. This review addresses day-length dependent variation in physiology and behavior, and presents the current understanding of the mechanisms supporting selective social relationships in meadow voles, with connections to lessons from other species.
Project description:Allan-Herndon-Dudley syndrome (AHDS) is a neurodevelopmental disorder that manifests as intellectual disability and motor developmental delay. Thyroid hormone transporter dysfunction due to SLC16A2 mutation is the underlying cause of this disorder. We identified a novel (P537del) and a recurrent (A150V) SLC16A2 mutation in Japanese AHDS patients from two different families. A150V co-segregated with S33P. Both patients showed similar clinical features including severe neurological features and delayed myelination. Thyroid function showed a common finding of elevated T3 levels. No clear genotype-phenotype correlation was observed in patients with SLC16A2 alterations.
Project description:Allan-Herndon-Dudley syndrome was among the first of the X-linked mental retardation syndromes to be described (in 1944) and among the first to be regionally mapped on the X chromosome (in 1990). Six large families with the syndrome have been identified, and linkage studies have placed the gene locus in Xq13.2. Mutations in the monocarboxylate transporter 8 gene (MCT8) have been found in each of the six families. One essential function of the protein encoded by this gene appears to be the transport of triiodothyronine into neurons. Abnormal transporter function is reflected in elevated free triiodothyronine and lowered free thyroxine levels in the blood. Infancy and childhood in the Allan-Herndon-Dudley syndrome are marked by hypotonia, weakness, reduced muscle mass, and delay of developmental milestones. Facial manifestations are not distinctive, but the face tends to be elongated with bifrontal narrowing, and the ears are often simply formed or cupped. Some patients have myopathic facies. Generalized weakness is manifested by excessive drooling, forward positioning of the head and neck, failure to ambulate independently, or ataxia in those who do ambulate. Speech is dysarthric or absent altogether. Hypotonia gives way in adult life to spasticity. The hands exhibit dystonic and athetoid posturing and fisting. Cognitive development is severely impaired. No major malformations occur, intrauterine growth is not impaired, and head circumference and genital development are usually normal. Behavior tends to be passive, with little evidence of aggressive or disruptive behavior. Although clinical signs of thyroid dysfunction are usually absent in affected males, the disturbances in blood levels of thyroid hormones suggest the possibility of systematic detection through screening of high-risk populations.
Project description:Allan-Herndon-Dudley syndrome (AHDS) is characterized by neuropsychomotor developmental delay/intellectual disability, neurological impairment with a movement disorder, and an abnormal thyroid hormone profile. This disease is an X-linked disorder that mainly affects men. We described a female patient with a de novo variant in the SLC16A2 gene, a milder AHDS phenotype, and a skewed X chromosome inactivation profile. We discuss the mechanisms associated with the expression of the phenotypic characteristics in female patients, including SLC16A2 gene variants and cytogenomic alterations, as well as preferential inactivation of the normal X chromosome.
Project description:Following the 2007-2009 financial crisis, governments around the world passed laws that marked the beginning of new period of enhanced regulation of the financial industry. These laws called for a myriad of new regulations, which in the U.S. are created through the so-called notice-and-comment process. Through examining the text documents generated through this process, we study the formation of regulations to gain insight into how new regulatory regimes are implemented following major laws like the landmark Dodd-Frank Wall Street Reform and Consumer Protection Act. Due to the variety of constituent preferences and political pressures, we find evidence that the government implements rules strategically to extend the regulatory boundary by first pursuing procedural rules that establish how economic activities will be regulated, followed by specifying who is subject to the procedural requirements. Our findings together with the unique nature of the Dodd-Frank Act translate to a number of stylized facts that should guide development of formal models of the rule-making process.