Allan-Herndon-Dudley Syndrome: a medical chimera

 A 10 month old boy came to me with the history of axial hypotonia, scissoring of lower limbs and dyskinetic movements for the past 6 months. 

His birth weight was 3.75 kg but despite a good appetite had poor weight gain and excessive sweating. His parents also noticed that the anterior fontanelle had closed by 6 months. 

His TSH was normal but he had an elevated fT3 and normal fT4. His free T3/T4 ratio was 4.13

This combination of developmental delay with dyskinesias in a boy with a free T3/T4 > 0.75 is classical of   Allan-Herndon-Dudley syndrome (AHDS).

The problem in AHDS is in the MCT8 gene. It codes for a protein which transports thyroid hormones across the blood brain barrier. In its absence T3 is unable to enter the brain and just a minuscule amount of T4 enters via another transporter coded by OATP1C1.

There is an excess of peripheral conversion of T4 to T3. What results is a peripheral thyrotoxicosis. But alas the brain is starving for thyroid hormones.

This lack of thyroid hormone inside the brain results in hypomyelination, developmental delay and dyskinesias. Systemically there is tachycardia, sweating and weight loss.

I sat down to see what is new in the therapy of this fascinating disease.

Merely giving T4 supplements aggravates the hyperthyroidism and is to be avoided.

Trials of a combination of T4 with propylthiouracil (PTU) stabilises the peripheral hyperthyroidism, allows a little T4 to enter the brain and improves weight gain. Unfortunately it does not improve the neurological functions significantly. Its drawback is the long term risk of agranulocytosis and liver failure with PTU.

A recent review of advances in therapeutics of AHDS describes the use of T3 analogs which don't require MCT8 to cross the BBB. Trials are on with three drugs- DITPA, TRIAC and sobetirome.

Work is also on with gene therapy and pharmacological chaperones ( Frontiers in Neurology April 2020) .https://doi.org/10.3389/fnins.2020.00380

An interesting study used intranasal T4 to bypass the block due to MCT8 deficiency but failed to raise thyroid hormone levels in the brain (PLOS ONE July 2020). https://doi.org/10.1371/journal.pone.0236113