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MCT8 Deficiency in Females
Stefan Groeneweg1, Ferdy S van Geest1, Floor van der Most1
1Academic Center for Thyroid Diseases, Department of Internal Medicine, Erasmus Medical Center, Erasmus University Rotterdam, 3015 GD Rotterdam, the Netherlands.
The Journal of Clinical Endocrinology and Metabolism
|May 27, 2025
Summary
Heterozygous pathogenic variants in SLC16A2 can cause neurocognitive and thyroid issues in females with MCT8 deficiency. Skewed X-chromosome inactivation is key in these presentations.
Area of Science:
- Genetics and Molecular Biology
- Endocrinology
- Neuroscience
Background:
- Monocarboxylate transporter 8 (MCT8) is crucial for thyroid hormone (TH) transport across the blood-brain barrier.
- Pathogenic variants in SLC16A2 cause MCT8 deficiency (Allan-Herndon-Dudley syndrome), typically affecting males due to X-linked inheritance.
- This syndrome is characterized by intellectual disability, motor deficits, and abnormal thyroid function tests.
Purpose of the Study:
- To investigate the clinical presentation and underlying genetic mechanisms of MCT8 deficiency in female patients.
- To analyze the impact of heterozygous pathogenic variants in SLC16A2 on TH transport and neurocognitive function in females.
- To highlight the role of X-chromosome inactivation in the manifestation of symptoms in female carriers.
Main Methods:
- Genetic analysis to identify heterozygous pathogenic variants in SLC16A2 in female patients.
- X-chromosome inactivation studies in patient-derived cells.
- Functional assessment of SLC16A2 variants using transfected cells and patient fibroblasts to evaluate TH transport capacity.
Main Results:
- Eight female patients with heterozygous pathogenic variants in SLC16A2 were identified, presenting with variable neurocognitive and behavioral issues, and abnormal TH levels.
- All identified missense variants demonstrated significantly reduced MCT8-mediated TH uptake in functional assays.
- Skewed X-chromosome inactivation was observed in all evaluated female patients, with impaired TH uptake in fibroblasts mirroring that of male patients.
Conclusions:
- Female patients with heterozygous pathogenic variants in SLC16A2 and skewed X-chromosome inactivation can exhibit diverse neurodevelopmental, behavioral, and thyroid function abnormalities.
- Testing for SLC16A2 genetic variants is recommended for female patients presenting with neurocognitive impairment and abnormal thyroid function tests.
- These findings expand the understanding of MCT8 deficiency and its phenotypic variability in females.
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