Allan-Herndon-Dudley syndrome (AHDS) is an X-linked disorder associated with intellectual disability and neuromuscular abnormalities. Typical features include flaccid muscle tone in infancy (infantile hypotonia), underdeveloped muscles, spastic paralysis of the lower extremities with dystonic or athetoid movements, and pronounced cognitive impairments.
The disorder is caused by mutations in the SLC16A2 gene. This gene encodes monocarboxylate transporter 8 (MCT8), which is responsible for transporting the thyroid hormone triiodothyronine (T3) to the brain.
The central pathophysiology of AHDS is based on impaired hormone transport:
This double maldistribution has profound effects on cognitive, motor and metabolic functions.
The disease is caused by mutations in the SLC16A2 gene (Xq13.2). It is inherited in an X-linked recessive manner. The syndrome can also arise spontaneously as a new mutation during foetal development, meaning that the affected child is the first family member with AHDS.
If a mutation is known to exist in the family, prenatal diagnosis is possible in male foetuses.
Since the mutation affects the X chromosome, AHDS occurs almost exclusively in males. Female carriers are considered asymptomatic in classical teaching. However, there is increasing evidence that individual heterozygous women may also develop mild or, in rare cases, more pronounced symptoms, especially in cases of unfavourable X inactivation.