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Allan-Herndon-Dudley syndrome

Allan-Herndon-Dudley syndrome (AHDS) is a disorder of brain development that causes moderate to severe intellectual disability and problems with movement. AHDS is caused by genetic variants in the SLC16A2 gene on the X chromosome. The SLC16A2 gene encodes (creates) MCT8, which is a protein necessary for transporting thyroid hormone from the blood into the brain. Without MCT8, thyroid hormone builds up to dangerously high levels in the blood while thyroid hormone levels in the brain are dangerously low. Thyroid hormone is needed in the brain for proper neurological (brain and spinal cord) development of a fetus during pregnancy. So, patients with mutations in SLC16A2 who cannot make MCT8 end up with various neurologic deficits that are present from birth. These deficits are classified together as AHDS1,2.

Males with AHDS often have impaired speech and limited ability to communicate, though this varies in severity from patient to patient. Males will also experience varying degrees of intellectual disability, and most will have difficulty walking and moving due to poor neuro-muscular development. Spasticity (increased muscle stiffness), hypotonia (weak muscle tone) and contractures (abnormal joint deformities that limit movement) are all common in patients with AHDS. The severity of symptoms depends on the severity (pathogenicity) of a patient’s gene mutation and how much thyroid hormone was able to be transported to the brain throughout development. Genetic mutations that cause complete loss of MCT8, with no thyroid hormone reaching the brain, will have significantly more impairment compared to those with some retained MCT8 function.

 

Females with AHDS

Females with variants in SLC16A2 on one X chromosome (heterozygotes) are usually asymptomatic carriers of AHDS. Approximately 25% of female carriers have abnormal thyroid hormone levels (high levels in their blood), however they typically are without any neurologic symptoms of disease, indicating that sufficient thyroid hormone was transported to the brain during development3. This is because having one normal X chromosome (with a normal copy of the SLC16A2 gene) is usually able to compensate for the mutated one.

Rarely, females can have mild to severe features of disease which is thought to be due to skewed X-inactivation (a majority of cells within affected females favoring the mutant X chromosome)3. One study in 2025 reported on 8 symptomatic females who were heterozygous for SLC16A2 variants4. These patients had variable degrees of intellectual disability and thyroid hormone irregularities on blood work. Two had severe, male-like disease, while the others had milder features of disease such as learning disabilities and attention deficits. Most of these females did not have the motor difficulties commonly seen in male patients. Of the 7 patients in this study who were tested for levels of X-inactivation, all 7 of them showed skewed levels. In contrast, asymptomatic carriers usually have balanced X-inactivation and normal MCT8 activity4.

While rare, several females have been reported to have the full features of severe disease like males with AHDS, with severe cognitive delay, no speech, hypotonia, contractures and abnormal thyroid hormone levels4-6. These cases are consistently found to have highly skewed X-inactivation or other rare genetic reasons for absence of the normal copy of the SLC16A2 gene.

Importantly, one small study looked at the effects of being an AHDS carrier on pregnancy, which is a time when thyroid hormone levels often become irregular7. They followed 2 women throughout pregnancy and found that one of them developed low thyroid hormone levels, so both were treated with supplemental thyroid hormone medication. All 3 of the babies that resulted from the pregnancies (none of whom had AHDS themselves) had normal thyroid function and appeared neurodevelopmentally normal. This study suggests that female carriers of AHDS should be monitored throughout pregnancy for the requirement of thyroid hormone medication, which may be necessary to protect against neurodevelopmental deficits in the child7.

Unfortunately, the percentage of female carriers of AHDS who develop signs or symptoms of disease is not known. While generally understood to be rare, it is believed to be under-diagnosed, as SLC16A2 mutations were historically not considered as a possible cause of disease in females4. Now that we are gaining a better understanding of the possibility of disease in females and have better access to genetic testing, improved data may exist in the coming years.

This page was last updated in July, 2026. Please note that research into females with this condition is limited and the number of reported cases is small. Decisions regarding your own health should be made in consultation with your medical provider.

  1. Allan-Herndon-Dudley syndrome: MedlinePlus Genetics. Accessed July 21, 2026. https://medlineplus.gov/genetics/condition/allan-herndon-dudley-syndrome/ 
  2. Charzewska A, Wierzba J, Iżycka-Świeszewska E, et al. Hypomyelinating leukodystrophies — a molecular insight into the white matter pathology. Clin Genet. 2016;90(4):293-304. doi:10.1111/cge.12811 
  3. Sarret C, Oliver Petit I, Tonduti D. Allan-Herndon-Dudley Syndrome. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, eds. GeneReviews®. University of Washington, Seattle; 1993. Accessed July 21, 2026. http://www.ncbi.nlm.nih.gov/books/NBK26373/ 
  4. Groeneweg S, van Geest FS, van der Most F, et al. MCT8 Deficiency in Females. J Clin Endocrinol Metab. 2025;111(1):e175-e184. doi:10.1210/clinem/dgaf311 
  5. Frints SGM, Lenzner S, Bauters M, et al. MCT8 mutation analysis and identification of the first female with Allan–Herndon–Dudley syndrome due to loss of MCT8 expression. Eur J Hum Genet. 2008;16(9):1029-1037. doi:10.1038/ejhg.2008.66 
  6. Sriram S, Shahid N, D DM, Lichter-Konecki U, Yatsenko SA, Garibaldi LR. Late diagnosis of the X-linked MCT8 deficiency (Allan–Herndon–Dudley syndrome) in a teenage girl with primary ovarian insufficiency. J Pediatr Endocrinol Metab. 2024;37(4):371-374. doi:10.1515/jpem-2023-0070 
  7. Ramos HE, Morandini M, Carré A, et al. Pregnancy in women heterozygous for MCT8 mutations: risk of maternal hypothyroxinemia and fetal care. Eur J Endocrinol. 2011;164(2):309-314. doi:10.1530/EJE-10-0679