The clinical importance of TH transporters was established by the discovery of mutations in the MCT8 gene, which is located on the X chromosome, as a cause of psychomotor retardation accompanied by TH abnormalities.[8, 9] Affected males display a severe delay in motor and neurological development. Soon after the description of the first patients, it was realized that the phenotype had similarities to the Allan–Herndon–Dudley syndrome (AHDS), the first X-linked mental retardation syndrome described in 1944. Genetic analysis in these families revealed that MCT8 mutations are the genetic basis of AHDS. To date, over 100 families have been reported with pathogenic mutations in MCT8.
Patients have cognitive impairments with intelligence quotient values mostly below 40. Many patients are unable to speak and are only able to communicate by nonverbal acts. Some patients have been reported to suffer from seizures. All patients have difficulties with swallowing. The consequent feeding problems are one of the reasons for the first referral. Hypotonia of the limbs in childhood progresses into spastic quadriplegia with advancing age. The severe axial hypotonia, which is manifested by a poor head control, persists into adulthood. Muscle hypoplasia, in particular of the quadriceps muscle, is observed in all patients. Most patients are unable to walk independently. At birth, height and weight are usually unremarkable. However, during childhood, weight declines below the third percentile in most patients.
Few patients reportedly have somewhat milder features. Some patients are able to walk without support and can communicate verbally. Patients with a less severe clinical phenotype typically have less abnormal thyroid parameters. MCT8 mutants of less severely affected patients also display residual activity in in vitro TH transport assays, suggesting a genotype–phenotype relationship in the AHDS. In general, female carriers do not exhibit neurological features. However, they have serum FT4 levels in between those in affected males and unaffected relatives.
Mechanisms of disease
The mechanisms behind the clinical and laboratory features of AHDS are only partially understood. As shown by in vitro transport assays, TH transport is largely or completely impaired by the MCT8 mutations identified. TH transport capacity is also largely reduced in fibroblasts from MCT8 patients. Thus, abnormal handling of TH transport appears as the basis for the disease.
Several mechanisms contribute to the low T4 levels. In Mct8 knockout (KO) mice, kidney T4 levels are increased despite the low serum T4 levels, suggesting that T4 is trapped in the kidney. At the same time, kidney (and liver) D1 expression is markedly increased, which should result in a prominent increase in peripheral T4 to T3 conversion. Recently, it was shown that MCT8 expression in the thyroid gland is required for TH secretion, which is therefore disturbed in Mct8 KO mice.[32, 33] The consequent accumulation of T4 within the thyroid gland when MCT8 is mutated may thus lead to increased intrathyroidal conversion to T3. This will favour an increased T3/T4 ratio in the thyroid, resulting in a net increase in T3 secretion via other efflux pathways. The important contribution of D1 in the thyroid and peripheral tissues to the high serum T3/T4 ratio in Mct8-deficient mice (and patients) is supported by findings that Mct8/Dio1 double KO mice have normal serum TH levels. Also, block-and-replace therapy of an AHDS patient with LT4 and the thyrostatic drug propylthiouracil (PTU), which also inhibits D1, normalized serum T3 concentrations. This was not the case when methimazole was used, which does not inhibit D1. The decreased serum rT3 levels are caused by reduced availability of its substrate T4 as well as by the elevated D1 activity, for which rT3 is the preferred substrate.
The high serum T3 levels induce thyrotoxic effects on peripheral tissues, which likely explain the progressive loss of muscle mass as well as the decline in body weight during childhood. Also, SHBG levels, which are T3 dependent and reflect liver thyroid state, are markedly elevated in AHDS patients. Although FT4 levels are low, TSH levels appear inappropriately high in the context of the high serum T3 concentrations, suggesting interference in the feedback of TH at the pituitary and/or hypothalamic level.
The neurological phenotype of AHDS patients is much less understood. The current hypothesis holds that derangement of TH homeostasis in the brain likely underlies the mechanism of disease in AHDS, because neuronal differentiation and myelination are TH-dependent processes. This entails a defect of T3 entry in MCT8-expressing neurons and, thus, deprivation of TH in specific brain regions and perhaps excessive accumulation of T3 in neurons which use other transporters for their T3 supply. MCT8 is also importantly expressed in capillaries and, thus, also appears important for transport of both T3 and T4 across the blood–brain barrier. Mct8 KO mice lack neurological features, despite largely impaired T3 uptake into the brain, while T4 uptake is preserved. Apparently, these mice employ compensatory mechanisms. Increased cerebral D2 activity in Mct8 KO mice may produce sufficient T3 for normal brain development. In addition, these animals likely express a specific T4 transporter, such as Oatp1c1, which mediates T4 transport across the BBB. This hypothesis is supported by a recent study of Oatp1c1 KO mice, which revealed markedly reduced cerebral T4 levels. Expression of Oatp1c1 in the mouse, but perhaps much less so in the human BBB, may well explain the differences in brain phenotype between mice and humans deficient in MCT8.
Altogether, AHDS patients exhibit clinical features caused by a combination of hyperthyroid and hypothyroid tissues. Thus, depending on expression of MCT8 or other TH transporters, tissues of AHDS patients are either deprived of TH (brain) or exposed to excess TH (liver and muscle).
Unfortunately, no effective treatment is available for AHDS patients at present. General supportive care should be provided, including adequate feeding support to avoid aspiration and anti-epileptic drugs to prevent seizures if necessary.
Given the low FT4 levels, LT4 suppletion was initiated in some patients with no beneficial effects on peripheral thyrotoxicity.[39, 40] Normalization of serum T4 and T3 levels was readily achieved in a few AHDS patients by block-and-replace therapy using PTU and LT4.[35, 41] This had some beneficial effects such as an increased body weight and reduction in SHBG levels. Hypothetically, cerebral regions that do not rely on MCT8 for their TH supply might also benefit from this treatment. However, treatment with PTU and LT4 did not result in an improvement in cognitive functions in these older patients of 16 and 37 years of age.
Effective therapy should not only normalize toxic TH effects in peripheral tissues but also normalize the disturbed TH signalling in brain. Some studies have been performed with the T3 analogues diiodothyropropionic acid (DITPA) and triiodothyroacetic acid (Triac, TA3) and the T4 analogue tetraiodothyroacetic acid (Tetrac, TA4).[42-44] TA4 is efficiently activated by D2 to TA3, and TA4 and TA3 are inactivated by D3, thus following the normal deiodination routes. It was shown in Mct8 KO mice made hypothyroid that TA4 was able to restore brain development. Studies in Mct8 KO mice with DITPA demonstrated the normalization of TH parameters and attenuation of the thyrotoxic state of peripheral tissues. Importantly, an improvement in several indices of TH action in brain was observed. These observations prompted a study of the possible beneficial effects of DITPA therapy in four AHDS patients, the results of which were published recently. The main consistent findings were a significant decrease in serum T3, with little change in serum T4 and TSH levels. The normalization of T3 levels appeared beneficial for the liver and heart as suggested by the decrease in SHBG levels and heart rate, respectively. Weight gain was noted in some patients but also a progressive weight loss in another patient. None of the patients showed improvement in psychomotor development.
Future strategies to define optimal treatment for AHDS patients may explore the use of alternative TH analogues. The above-mentioned studies in AHDS patients all have in common that these therapies were carried out in patients in whom impaired brain development is likely irreversible. Therefore, it is important to diagnose MCT8 mutations as early as possible.