MCT8 deficiency in a patient with a novel frameshift variant in the SLC16A2 gene

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Abstract

MCT8 deficiency is an X-linked recessive disorder. We report the case of a 2-year-old Japanese boy with MCT8 deficiency caused by a novel frameshift variant, NM_006517.5(SLC16A2_v001):c.966dup [p.(Ile323Hisfs*57)]. He presented no head control and spoke no meaningful words, indicating severe developmental delay. Although missense or in-frame mutations of SLC16A2 are usually related to milder phenotypes and later-onset pyramidal signs, loss-of-function mutations are expected to cause severe clinical symptoms.

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Association between mutations in a thyroid hormone transporter and severe X-linked psychomotor retardation.

Edith C H Friesema, Annette Grueters, Heike Biebermann … (2004)

Monocarboxylate transporter 8 (MCT8) is a thyroid hormone transporter, the gene of which is located on the X chromosome. We tested whether mutations in MCT8 cause severe psychomotor retardation and high serum triiodothyronine (T3) concentrations in five unrelated young boys. The coding sequence of MCT8 was analysed by PCR and direct sequencing of its six exons. In two patients, gene deletions of 2.4 kb and 24 kb were recorded and in three patients missense mutations Ala150Val, Arg171 stop, and Leu397Pro were identified. We suggest that this novel syndrome of X-linked psychomotor retardation is due to a defect in T3 entry into neurons through MCT8, resulting in impaired T3 action and metabolism.

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Neuronal 3',3,5-triiodothyronine (T3) uptake and behavioral phenotype of mice deficient in Mct8, the neuronal T3 transporter mutated in Allan-Herndon-Dudley syndrome.

Eva K. Wirth, Stephan Roth, Cristiane Blechschmidt … (2009)

Thyroid hormone transport into cells requires plasma membrane transport proteins. Mutations in one of these, monocarboxylate transporter 8 (MCT8), have been identified as underlying cause for the Allan-Herndon-Dudley syndrome, an X-linked mental retardation in which the patients also present with abnormally high 3',3,5-triiodothyronine (T(3)) plasma levels. Mice deficient in Mct8 replicate the thyroid hormone abnormalities observed in the human condition. However, no neurological deficits have been described in mice lacking Mct8. Therefore, we subjected Mct8-deficient mice to a comprehensive immunohistochemical, neurological, and behavioral screen. Several behavioral abnormalities were found in the mutants. Interestingly, some of these behavioral changes are compatible with hypothyroidism, whereas others rather indicate hyperthyroidism. We thus hypothesized that neurons exclusively dependent on Mct8 are in a hypothyroid state, whereas neurons expressing other T(3) transporters become hyperthyroid, if they are exposed directly to the high plasma T(3). The majority of T(3) uptake in primary cortical neurons is mediated by Mct8, but pharmacological inhibition suggested functional expression of additional T(3) transporter classes. mRNAs encoding six T(3) transporters, including L-type amino acid transporters (LATs), were coexpressed with Mct8 in isolated neurons. We then demonstrated Lat2 expression in cultured neurons and throughout murine brain development. In contrast, LAT2 is expressed in microglia in the developing human brain during gestation, but not in neurons. We suggest that lack of functional complementation by alternative thyroid hormone transporters in developing human neurons precipitates the devastating neurodevelopmental phenotype in MCT8-deficient patients, whereas Mct8-deficient mouse neurons are functionally complemented by other transporters, for possibly Lat2.

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Genetics and phenomics of thyroid hormone transport by MCT8.

Edith C.H. Friesema, W. Edward Visser, Theo J. Visser (2010)

Thyroid hormone (TH) is crucial for the development of different organs, in particular the brain, as disturbances in TH supply cause severe neurological abnormalities. TH transporters are necessary for the intracellular availability of TH to have access to the deiodinases and nuclear receptors inside the cell. The clinical importance of TH transporters is dramatically shown in patients with mutations in MCT8, suffering from severe X-linked psychomotor retardation in combination with disturbed TH levels, especially high serum T(3) levels, now referred as Allan-Herndon-Dudley Syndrome (AHDS). Worldwide >45 families have now been identified with MCT8 mutations. Most MCT8 mutations result in a complete loss of TH transport function when tested in vitro, but some mutations show significant residual activity and are associated with a somewhat milder clinical phenotype. It is difficult to identify MCT8 patients only on the basis of the clinical characteristics of X-linked mental retardation. Therefore, the criterion for MCT8 mutation screening in these patients is the profile of increased T(3) and low-normal to low FT(4) serum levels. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.