Which are the causes of Allan-Herndon-Dudley Syndrome?

Allan-Herndon-Dudley Syndrome (AHDS) is a rare genetic disorder that primarily affects the development and function of the brain. It is also known as MCT8 deficiency, referring to the specific gene mutation that causes the syndrome. AHDS is inherited in an X-linked recessive manner, meaning it primarily affects males.

The main cause of Allan-Herndon-Dudley Syndrome is a mutation in the SLC16A2 gene, which provides instructions for producing a protein called monocarboxylate transporter 8 (MCT8). This protein plays a crucial role in transporting thyroid hormones into cells throughout the body, including the brain. The mutation in the SLC16A2 gene leads to a dysfunctional or absent MCT8 protein, resulting in impaired thyroid hormone transport.

Thyroid hormones are essential for the normal development and function of various organs and tissues, particularly the brain. They regulate metabolism, growth, and differentiation of cells. In individuals with AHDS, the lack of functional MCT8 protein prevents adequate transport of thyroid hormones into brain cells, leading to a disruption in their normal development and function.

Some of the key factors contributing to the development of Allan-Herndon-Dudley Syndrome include:

1. Genetic Mutation: The mutation in the SLC16A2 gene is the primary cause of AHDS. This mutation is typically inherited from the mother, who is usually an unaffected carrier of the altered gene. Sons of carrier mothers have a 50% chance of inheriting the mutated gene and developing AHDS.



2. X-Linked Recessive Inheritance: AHDS follows an X-linked recessive pattern of inheritance. This means that the mutated gene is located on the X chromosome. Since males have one X chromosome and females have two, males are more commonly affected by AHDS. Females can be carriers of the mutated gene but are typically unaffected due to the presence of a normal copy of the gene on their other X chromosome.



3. Impaired Thyroid Hormone Transport: The dysfunctional or absent MCT8 protein in individuals with AHDS leads to impaired transport of thyroid hormones, particularly triiodothyronine (T3), into brain cells. This disruption in thyroid hormone availability during critical periods of brain development contributes to the neurological abnormalities observed in AHDS.



4. Disrupted Brain Development: The inadequate supply of thyroid hormones to the developing brain affects its structure and function. The severity of brain abnormalities can vary among individuals with AHDS, leading to a wide range of symptoms and disabilities. The specific mechanisms by which disrupted thyroid hormone transport affects brain development are still being studied.

It is important to note that Allan-Herndon-Dudley Syndrome is a complex disorder with various factors influencing its manifestation and severity. Ongoing research aims to further understand the underlying mechanisms and develop potential treatments or interventions to improve the quality of life for individuals affected by AHDS.