Defective thyroid hormone transport to the brain leads to astroglial alterations.

Allan-Herndon-Dudley syndrome (AHDS) is a rare X-linked disorder that causes severe neurological damage, for which there is no effective treatment. AHDS is due to inactivating mutations in the thyroid hormone transporter MCT8 that impair the entry of thyroid hormones into the brain, resulting in cerebral hypothyroidism. However, the pathophysiology of AHDS is still not fully understood and this is essential to develop therapeutic strategies.

Insights on the role of thyroid hormone transport in neurosensory organs and implication for the Allan-Herndon-Dudley syndrome.

Thyroid hormones play an important role during the development and functioning of the different sensory systems. In order to exert their actions, thyroid hormones need to access their target cells through transmembrane transporter proteins, among which the monocarboxylate transporter 8 (MCT8) stands out for its pathophysiological relevance. Mutations in the gene encoding for MCT8 lead to the Allan-Herndon-Dudley syndrome (AHDS), a rare disease characterised by severe neuromotor and cognitive impairments.

Neurovascular unit disruption and blood-brain barrier leakage in MCT8 deficiency.

Background: The monocarboxylate transporter 8 (MCT8) plays a vital role in maintaining brain thyroid hormone homeostasis. This transmembrane transporter is expressed at the brain barriers, as the blood-brain barrier (BBB), and in neural cells, being the sole known thyroid hormone-specific transporter to date. Inactivating mutations in the MCT8 gene (SLC16A2) cause the Allan-Herndon-Dudley Syndrome (AHDS) or MCT8 deficiency, a rare X-linked disease characterized by delayed neurodevelopment and severe psychomotor disorders.

A CRISPR/Cas9-engineered avatar mouse model of monocarboxylate transporter 8 deficiency displays distinct neurological alterations.

Inactivating mutations in the specific thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to an X-linked rare disease named MCT8 deficiency or Allan-Herndon-Dudley Syndrome. Patients exhibit a plethora of severe endocrine and neurological alterations, with no effective treatment for the neurological symptoms. An optimal mammalian model is essential to explore the pathological mechanisms and potential therapeutic approaches.

Deficient thyroid hormone transport to the brain leads to impairments in axonal caliber and oligodendroglial development.

Mutations in the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to profound brain alterations, including myelination impairments, in humans. We aimed to further explore the pathophysiological mechanisms underlying the MCT8 deficiency-associated myelination impairments to unravel new biomarkers and therapeutic targets. We have performed brain histological analysis on an MCT8-deficient subject and histological, ultrastructural, and magnetic resonance imaging (MRI) analysis in the brain of a mouse model of the syndrome, lacking MCT8 and enzyme deiodinase type 2 (DIO2, Mct8/Dio2 KO).

Thyroid hormone availability in the human fetal brain: novel entry pathways and role of radial glia.

Thyroid hormones (TH) are crucial for brain development; their deficiency during neurodevelopment impairs neural cell differentiation and causes irreversible neurological alterations. Understanding TH action, and in particular the mechanisms regulating TH availability in the prenatal human brain is essential to design therapeutic strategies for neurological diseases due to impaired TH signaling during neurodevelopment. We aimed at the identification of cells involved in the regulation of TH availability in the human brain at fetal stages.