Clinical Features

The syndrome of resistance to thyroid hormone (RTH) is characterized by elevated circulating levels of free thyroid hormones together with nonsuppressed pituitary TSH secretion. It reflects resistance to thyroid hormone action in the hypothalamic-pituitary-thyroid (HPT) axis and is accompanied by variable refractoriness in peripheral tissues.

RTH was first described in 1967 in two siblings who were clinically euthyroid despite high circulating thyroid hormone levels. The siblings exhibited several other abnormalities, including deaf-mutism, stippled femoral epiphyses with delayed bone maturation and short stature, and dysmorphic facies, winging of the scapulae, and pectus carinatum.³ It is now clear that some of these features are unique to this kindred in whom the disorder was recessively inherited. The majority of RTH cases that have been subsequently described are dominantly inherited, with a highly variable clinical phenotype. Affected subjects are either asymptomatic or have nonspecific symptoms and may be noted to have a goiter, prompting thyroid function tests that suggest the diagnosis. In these individuals, classified as exhibiting generalized resistance to thyroid hormone (GRTH), the high thyroid hormone levels are thought to compensate for ubiquitous tissue resistance, resulting in a euthyroid state. In contrast, a smaller number of individuals (around 15%) who share the same biochemical phenotype exhibit clinical features of thyrotoxicosis. In adults, these can include weight loss, tremor, palpitations, insomnia, and heat intolerance; in children, failure to thrive, accelerated growth, and hyperkinetic behavior have also been noted. When this clinical entity was first described, patients were thought to exhibit “selective” pituitary resistance to thyroid hormone (PRTH) action, with preservation of normal hormonal responses in peripheral tissues,⁴ but it is now recognized that peripheral resistance (typically hepatic) to hormone action is present even in these subjects. Less commonly, hypothyroid features such as growth retardation, delayed dentition, and bone age in children or asthenia and hypercholesterolemia in adults have been observed in RTH and may even coexist with thyrotoxic symptoms in the same individual.⁵ Taken together, these observations suggest that the clinical features of this disorder are influenced by the degree of refractoriness of peripheral tissues to high circulating levels of free thyroid hormones.

The estimated prevalence of RTH is 1 in 50,000 live births; the disorder can be diagnosed neonatally by screening with a combination of TSH and free T₄ measurements.⁶ Over 700 cases of RTH (from more than 250 families) have now been described worldwide, enabling clinical characteristics of this disorder to be defined more precisely.

Molecular Genetics

Properties of Mutant Receptors

Consonant with their location in the hormone-binding domain, the majority of receptor mutants identified in RTH exhibit moderate or markedly reduced T₃ binding; consequently, their ability to activate or repress target gene expression is impaired.^54,55 A subset of RTH mutations associated with markedly abnormal thyroid function in vivo and altered transcriptional function in vitro (but little impairment in ligand binding) have been described. Such natural mutations involve residues that mediate receptor interaction with transcriptional coactivators.^39,56 In the first RTH family described, with the recessively inherited form of the disorder, the two affected siblings were found to be homozygous for a complete deletion of both alleles of the TRβ receptor gene.⁵⁷ Importantly, the obligate heterozygotes in this family harboring a deletion of one TRβ allele were completely normal with no evidence of thyroid dysfunction. This suggested that simple deficiency of a functional β receptor, as a consequence of the single deleted TRβ allele, was insufficient to generate the resistance phenotype. This led to the hypothesis that the heterozygous mutant receptors in dominantly inherited RTH were not simply functionally impaired but also capable of inhibiting wild-type receptor action. Studies confirmed that when coexpressed, the mutant proteins are able to inhibit the function of their wild-type counterparts in a dominant-negative manner.^58,59 Further clinical and genetic evidence supporting this notion have been provided by two rare examples of RTH. In the first, a childhood case, severe resistance with marked developmental delay and growth retardation associated with cardiac hyperthyroidism was ultimately fatal due to heart failure following septicemia; this individual was homozygous for a mutation (Δ337T) in both alleles of the TRβ gene.⁶⁰ In the second more recently reported case, the affected subject also exhibited a particularly severe clinical phenotype and was found to be either homozygous or hemizygous for a TRβ mutation (I280S).⁶¹ Presumably, the extreme phenotype observed in both cases reflected not only the absence of normally functioning TRβ but the added dominant-negative inhibitory effect of mutant β receptors.

Functional studies of mutant receptors indicate that although they are transcriptionally impaired and dominant-negative inhibitors, their ability to bind DNA and form heterodimers with RXR is preserved.^54,55 Conversely, it has been shown that the introduction of additional artificial mutations that abolish DNA binding or heterodimer formation abrogates the dominant-negative activity of mutant receptors in vitro.^55,62,63 Mice heterozygous for a TRβ mutation lacking DNA binding do not exhibit RTH.⁶⁴ It has also been suggested that the ability of mutant receptors in RTH to repress or “silence” basal gene transcription is likely to be an important factor contributing to their dominant-negative potency. Non-T₃-binding mutants exhibit constitutive silencing function, particularly when bound to DNA as homodimers, which cannot be relieved by ligand. Conversely, RTH mutants with impaired homodimerization properties are weaker dominant-negative inhibitors.⁶⁵ With the identification of corepressors, these observations have been extended to show that some RTH mutants either bind corepressor more avidly when unliganded or fail to dissociate fully from corepressor upon T₃ binding.⁶⁶ Furthermore, artificial mutations that abolish corepressor binding abrogate the dominant-negative activity of RTH receptor mutants.⁶⁶ It has also been suggested that corepressors mediate basal activation of negatively regulated gene promoters (e.g., thyrotropin-releasing hormone [TRH], TSH-α, TSH-β) by unliganded TR.⁶⁷ An unusual RTH receptor mutant (R383H) exhibits both delayed T₃-dependent corepressor release and impaired hormone-dependent negative transcriptional regulation.⁶⁸ Given the pivotal role of negatively regulated target genes in the pathogenesis of RTH, aberrant corepressor recruitment or release may well prove to be the critical receptor abnormality in this disorder.

Together, these observations allow a model to be constructed (Fig. 23-4) in which occupancy of target gene binding sites by mutant receptor-corepressor complexes mediates dominant-negative inhibition by RTH mutants. Mapping of the three clusters of RTH receptor mutations identified hitherto on the crystal structure of the ligand-binding domain of TRβ⁶⁹ provides insights into structure-function relationships in TR (see Fig. 23-3). As expected from their impaired ligand-binding properties, most mutations are located around the hormone-binding cavity, and receptor regions mediating DNA binding, dimerization, and corepressor interaction are devoid of naturally occurring mutations, possibly because they lack dominant-negative activity and therefore elude discovery—being biochemically and clinically silent.

Pathogenesis of Variable Resistance

Genetic and functional evidence suggests that the ability to exert a dominant-negative effect on target genes within the HPT axis is a fundamental property of RTH receptor mutants, generating the abnormal thyroid function characteristic of the disorder. Indeed, some studies indicate that for a subset of RTH mutants, there is a correlation between their functional impairment in vitro and the degree of central pituitary resistance, as measured by the magnitude of elevation in serum-free T₄ in vivo.^70,71 On this biochemical background, the heterogeneous clinical phenotype may be due to differing degrees of peripheral resistance in different individuals as well as variable resistance in different tissues within a single subject. A number of factors may contribute to such variable tissue resistance.

One important contributory element may be the differing tissue distributions of receptor isoforms. The hypothalamus/pituitary, and liver express predominantly TRβ2 and TRβ1 receptors, respectively, and TRα1 is the major species detected in myocardium. Mutations in the TRβ gene are likely to be associated with pituitary and liver resistance, as exemplified by nonsuppressed TSH and normal sex hormone–binding globulin (SHBG) levels seen in patients, whereas the tachycardia and cardiac hyperthyroidism in some cases may represent retention of myocardial sensitivity to high circulating thyroid hormones acting via a normal α receptor. Another factor that may influence the degree of tissue resistance is the relative expression of mutant versus wild-type TRβ alleles. One study has suggested that both alleles are equally expressed⁷²; another showed marked differences in the relative levels of wild-type and mutant receptor messenger RNA in skin fibroblasts from two RTH cases.⁷³ In one of these individuals, a temporal variation in expression of the mutant allele in fibroblasts appeared to correlate with the degree of skeletal tissue resistance. The dominant-negative inhibitory potency of mutant receptors has been shown to differ depending on target gene promoter context^55,74 and is a further variable that may influence the degree of resistance. Finally, factors unrelated to the TRβ gene might influence the phenotype. For example, a deleterious R316H mutation was associated with normal thyroid hormone levels in some members of one kindred⁷⁵ but clearly abnormal thyroid function in an unrelated family,³⁸ suggesting that other genetic variables can modulate the effect of receptor mutations.

While the absence or presence of overt thyrotoxic features allows patients to be classified as either GRTH or PRTH—a clinical definition that will probably remain useful as a guide to the most appropriate form of treatment—studies indicate that there is some overlap of features between the two forms of the disorder. For example, there are no significant differences in age, sex ratio, frequency of goiter, thyroid function, or clinical features between patients with GRTH or PRTH.⁷⁶ Importantly, features such as tachycardia, hyperkinetic behavior, and emotional disturbance have been documented in individuals with GRTH.⁷⁶ Conversely, serum SHBG, a hepatic index of thyroid hormone action, is almost invariably normal in patients with PRTH, suggesting that tissue resistance is not solely confined to the HPT axis in this group of patients.⁷⁷

Attempts to correlate the phenotype of RTH with the nature of the underlying TRβ mutation have been confounded by three factors: (1) the relative imprecision of clinical criteria used to define GRTH and PRTH; (2) the apparent temporal variation in hyperthyroid features in some RTH cases, such that thyrotoxic symptoms and signs can develop and disappear spontaneously when individuals are followed over several years⁷⁶; and (3) the relatively small number of patients with any given mutation that have been identified. Nevertheless, some interesting correlations have emerged from the published literature. The first patient reported to have PRTH⁴ was found to harbor an R338W receptor mutation,⁴¹ and the same phenotype has been described in the majority of individuals with this or similar substitutions at this codon.^38,42 Interestingly, when tested in vitro, this mutant exhibits dominant-negative activity with the negatively regulated pituitary TSH α subunit gene promoter, but it is a relatively poor inhibitor of wild-type receptor action in other promoter contexts.⁵⁵ When introduced into other RTH receptor–mutant backgrounds, this mutation weakens their dominant-negative potency on positively regulated reporter genes.⁷⁸ A patient with the R383H receptor defect, which is impaired mainly in regulation of TRH and TSH genes, exhibited predominant central resistance following T₃ administration,⁷⁹ and the R429Q mutation, with similar functional properties, may also occur more frequently in association with PRTH. Some receptor mutants (R338W or L, V349M, R429Q, I431T) associated with PRTH are either more deleterious⁸⁰ or exert a greater dominant-negative inhibitory effect in a TRβ2 than a TRβ1 context.⁸¹A receptor mutation that selectively fails to bind NCoR but not SMRT is associated with PRTH.⁸²

Animal Models

The generation of various receptor knockout mice has greatly enhanced our understanding of the physiologic roles of individual TR isoforms, particularly in regulation of the HPT axis. For example, homozygous TRβ gene deletion (TRβ KO), leading to absence of both TRβ1 and TRβ2 isoforms, increased circulating thyroid hormone levels approximately threefold,²⁴ whereas deletion of the TRα1 isoform had no effect.⁸³ When only the TRβ2 isoform was deleted, the biochemical phenotype was similar to that of TRβ KO, suggesting that TRβ2 is the key isoform mediating feedback regulation of hypothalamic TRH and pituitary TSH output.⁸⁴ Importantly, many of the features in the recessively inherited cases of RTH associated with a deletion encompassing the human TRβ gene were recapitulated in TRβ KO mice.²⁴ Homozygous animals exhibited elevated serum thyroid hormones and an inappropriately elevated TSH, while their heterozygous littermates were biochemically normal. To explore the properties of mutant TRβs in RTH in vivo, several groups have developed transgenic mice in which dominant-negative TRβ mutants have been overexpressed either ubiquitously⁸⁵ or selectively in tissues.^86,87 These models have provided valuable insights into mutant receptor function and pathophysiologic mechanisms that mediate RTH. For example, selective targeting of an RTH mutant to the pituitary using a tissue-specific promoter generated transgenic mice with elevated TSH but only marginally raised T₄ levels. This suggests that the additional dominant-negative effect of mutant receptors on the hypothalamic TRH gene might be required to produce the full biochemical phenotype.⁸⁷ In contrast, ubiquitous transgenic mutant TRβ expression resulted in an animal model with more generalized tissue resistance; these mice displayed decreased body weight, hyperactivity, and learning deficit, which are recognized features of the human syndrome.⁸⁵ An important limitation of these animal models is that expression of the mutant receptor transgene is not controlled by the TRβ gene promoter, so the pattern of mutant receptor expression or the resulting phenotype might not correspond with that of human RTH. Transgenic mice in which either a frameshift mutation involving 14 carboxy-terminal amino acids (TRβ PV)⁸⁸ or an in-frame deletion of a threonine residue (Δ337T)⁸⁹ have been introduced into the TRβ gene locus have also been generated. Both these TRβ mutations have been identified in human RTH, and the mutant receptors exhibit markedly impaired transcriptional activation and potent dominant-negative activity in vitro. Extensive characterization of the phenotype of TRβ PV^88,90 and Δ337T mice has indicated that these animal models recapitulate the human RTH phenotype, with heterozygous mice exhibiting mild to moderate resistance and homozygous littermates severe resistance in the HPT axis. Interestingly, when compared with TRβ KO mice, thyroid hormone and TSH levels were significantly more elevated in the Δ337T knock-in animals, supporting the notion that dominant-negative inhibition by the mutant receptor antagonizes residual TRβ1 activity in the HPT axis. Both heterozygous and homozygous Δ337T mice exhibited abnormalities of vestibulomotor function which correlated with an overall reduction in cerebellar size and in the area of the Purkinje cell layer.

Studies with TRβ PV mice have provided insights into the molecular basis for dominant-negative activity in vivo, confirming that mutant receptor homodimers and heterodimers compete with wild-type TRβ for binding to target gene TREs. The interplay of receptor isoform predominance (e.g.,TRβ1 in liver, TRα1 in heart) together with the promoter context of target gene TREs can influence the degree of dominant-negative inhibition observed in different tissues.⁹⁰ Interestingly, crossing TRβ PV mice with SRC-1 KO animals enhanced the degree of resistance in the HPT axis in heterozygous TRβ PV mice, providing evidence that coactivator “availability” can also modulate mutant TRβ action in vivo.⁹¹ Metastatic thyroid carcinoma was an unexpected finding in older, homozygous TRβ PV mutant mice but has not been observed in their heterozygous counterparts.⁹² Mice harboring a TRβ mutation (R429Q) associated with PRTH exhibit greater dysregulation of negative versus positively regulated target genes, providing a mechanism for correlation of some TRβ genotypes with phenotype.⁹³

Finally, it is appropriate to include a brief description of mice harboring mutations in the TRα gene locus. Selective knockout of the TRα1 isoform was associated with low or normal serum thyroid hormones, a decreased heart rate, and lower body temperature—a phenotype quite dissimilar to RTH.⁸³ Knock-in mice with heterozygous point mutations in TRα that correspond to naturally occurring TRβ mutations in RTH have either normal or mildly reduced thyroid hormone levels,^95–98 with additional features including bradycardia, growth retardation, CNS abnormalities,^95,98 and insulin resistance,⁹⁶ which may provide important clues to the probable phenotype of a homologous human disorder.⁹⁷

Management

The management of RTH is difficult, since variable resistance makes it difficult to maintain euthyroidism in all tissues. In general, the presence or absence of hyperthyroid features is a useful guide to the need for therapy. In most individuals, the receptor defect is compensated by high circulating thyroid hormone levels, leading to a euthyroid state not associated with abnormalities other than a small goiter. Attempts to treat the biochemical abnormality with surgery or radioiodine are usually unsuccessful, with recrudescence of the goiter (often nodular in nature) and disruption of the thyroid axis.¹⁴ Certain circumstances such as hypercholesterolemia in adults or developmental delay and growth retardation in young children may warrant the administration of supraphysiologic doses of L-T₄ to overcome a higher degree of resistance in certain tissues. Although successful in some cases,¹⁴ such therapy needs careful monitoring of indices of thyroid hormone action (e.g., SHBG, heart rate, BMR, bone markers) to avoid the adverse cardiac effects or excess catabolism associated with thyroxine overtreatment. Inappropriate thyroid ablation also renders the RTH patient hypothyroid, with elevated TSH levels and risk of thyrotroph hyperplasia,³¹ and is another context in which supraphysiologic thyroxine replacement is indicated. Alternate-day administration of L-T₃ in supraphysiologic dosage led to significant regression of goiter without inducing thyrotoxic symptoms in one case.⁹⁹

In contrast, a general reduction in thyroid hormone levels may be of benefit in the management of patients with thyrotoxic symptoms. However, the administration of conventional antithyroid drugs usually causes a further rise in serum TSH levels that stimulates thyroid enlargement and may also induce thyrotroph hyperplasia, with a theoretic risk of developing autonomous neoplasms at either site. Accordingly, agents that inhibit pituitary TSH secretion but are relatively devoid of peripheral thyromimetic effects are administered to reduce thyroid hormone levels. The most widely used example is the thyroid hormone analog 3,5,3′-triiodothyroacetic acid (TRIAC), which has been shown to be beneficial in both childhood and adult cases.100–102 This compound has a number of interesting properties that make it an attractive therapeutic option in RTH: (1) it exerts predominantly pituitary and hepatic thyromimetic effects in vivo,¹⁰³ target tissues that are relatively refractory to thyroid hormones in RTH; (2) it has greater affinity, potency, and activity than T₃ for TRβ¹⁰⁴; and (3) it exhibits a higher affinity for TRβ than TRα in vitro.¹⁰⁵ A daily dose of 1.4 to 2.8 mg is generally used, and one study has suggested that twice daily administration might be optimal in inhibiting TSH secretion.¹⁰⁶ TRIAC has been successfully used in pregnancy to control maternal thyrotoxic symptoms but may have induced fetal goiter.¹⁰⁷ Treatment with TRIAC is not always effective, however,¹⁰⁸ and dextrothyroxine is another agent that has been shown to be useful in some cases.^109,110 If these compounds fail, the dopaminergic agent, bromocriptine,¹¹¹ or the somatostatin analog, octreotide,¹¹² may be administered, but past experience indicates that TSH secretion escapes the inhibitory effects of both bromocriptine^100,111 and octreotide.¹¹³ In view of the spontaneous variation in thyrotoxic symptoms in RTH, periodic cessation of thyroid hormone–lowering therapy and reevaluation of the clinical status of the patient is advisable. In rare circumstances such as severe thyrotoxic cardiac failure associated with RTH, thyroid ablation followed by subphysiologic thyroxine replacement may be indicated.

The treatment of thyrotoxic features (e.g., failure to thrive) in childhood RTH also requires careful monitoring to ensure that any reduction in thyroid hormone levels is not associated with growth retardation or adverse neurologic sequelae. Indeed, control of cardiac and sympathomimetic manifestations with β-blockade may be the safest course in this context. One study reported that L-T₃ therapy improved hyperactivity in nine children with ADHD and RTH, including three individuals who were unresponsive to methylphenidate.¹¹⁴

The therapeutic potential of TRIAC in RTH could be limited by the nature of the TRβ mutation, with some mutant receptors being less responsive, such that the dose of TRIAC required to activate mutant TRβ function is associated with unwanted TRα-mediated toxicity (e.g., tachycardia). Accordingly, the identification of compounds with higher affinity and selective agonist activity for mutant TRβ than for normal TRβ or TRα would represent a major therapeutic advance: TRβ-selective thyromimetics (e.g., GC1, KB2115) are being developed and may have utility in treating some abnormalities (e.g., dyslipidemia) in RTH.^115,116 HY1, an analog of GC1, is five times more potent with an R320C TRβ mutant than wild-type TRβ, suggesting that it may indeed be feasible to design hormone analogs that selectively overcome abnormal mutant receptor function without further activating normal β or α receptors.¹¹⁷ Rational molecular design has also led to the development of TR isoform–selective antagonists that may also be useful in, for example, controlling TRα-mediated toxic symptoms in RTH.¹¹⁸

Clinical Features

Worldwide, at least 50 families have been reported in which males are affected by severe psychomotor retardation associated with a particular combination of abnormal serum thyroid hormone levels. In 1944, long before thyroid involvement was suspected, the first description of this syndrome of X-linked mental retardation (XLMR) in a large family was published by Allan, Herndon, and Dudley.¹¹⁹ Since then, this disorder has been typically referred to as the Allan-Herndon-Dudley syndrome (AHDS). Only 60 years later was it realized that patients with AHDS also have abnormal thyroid function tests.^120–122

Usually, patients with AHDS are born at term after an uncomplicated pregnancy, with a normal birthweight, body length, and head circumference. During the first 6 months, general hypotonia is noticed. During development, truncal hypotonia persists, resulting in poor head control, whereas distal hypotonia progresses into spasticity. Growth is relatively normal, but final body length is reduced, and body weight is usually extremely low with obvious signs of muscle wasting. There is also progressive microcephaly. In the first 2 years of life, brain MRI shows delayed myelination, but this normalizes in subsequent years. Based on the delayed myelination, this combination of clinical features has also been referred to as Pelizaeus-Merzbacher-like disorder (PMLD).¹²³

Although the clinical phenotype is somewhat milder in some families, AHDS patients are usually incapable of sitting, standing, or walking independently and do not develop any speech. They are severely mentally retarded, with IQ values below 40. Feeding is a problem in AHDS patients; they have swallowing difficulties, and aspiration is a frequent cause of pneumonia. Patients with AHDS usually have a friendly nature. Recent reviews provide a detailed description of the clinical features of patients with AHDS.123–126

In addition to severe psychomotor retardation, AHDS patients have a characteristic combination of abnormal serum thyroid hormone levels.¹²⁵ This is also observed in a subset of patients with PMLD.¹²³ Both T₄ and free T₄ levels are either low-normal or clearly reduced, whereas serum T₃ and free T₃ are markedly elevated, and rT₃ is always low. Consequently, circulating T₃/T₄ and T₃/rT₃ ratios are markedly elevated. Although within the normal range, mean serum TSH levels in AHDS patients are about twice that in healthy controls. Serum SHBG levels are markedly elevated, and several studies have reported raised serum lactate in young patients.^127,128

Molecular Genetics

In all male patients with the characteristic combination of psychomotor retardation and abnormal serum thyroid hormone levels, different mutations in the monocarboxylate transporter 8 (MCT8) gene have been identified (Table 23-4). Both MCT8 and the highly homologous protein, MCT10, have been shown to be specific and active thyroid hormone transporters, although MCT10 is also capable of transporting aromatic amino acids.^129–131 These proteins belong to a wider family of MCT transporters, so named because MCTs 1 to 4 have been shown to facilitate transport of monocarboxylates such as lactate and pyruvate.¹³² The function of most other MCTs is as yet unknown.

MCT8 and MCT10 have identical gene structures; both consist of six exons and five introns, with a particularly long first intron (~100 kb). The MCT10 gene is located on chromosome 6q21-q22, encoding a protein of 515 amino acids. The MCT8 gene is located on chromosome Xq13.2 and has two possible translation start sites, generating either 613 (long) or 539 (short) amino acid protein products (Fig. 23-5). The significance of the N-terminal extension in the long form of the MCT8 protein (shown in light gray in Fig. 23-5) remains to be elucidated. All in vitro studies of the function of wild-type and mutated MCT8 have been carried out in the short protein context. Like MCT10, MCT8 has 12 putative transmembrane domains (TMDs), with both the N-terminal and C-terminal ends of the protein being located intracellularly. The amino acids that are identical and occupy corresponding positions in MCT8 and MCT10 are highlighted (see Fig. 23-5), showing that homology between these proteins is particularly high in their TMDs.

MCT8 mutations have now been identified in over 50 families with AHDS, and the majority of them are listed in Table 23-4. These mutations include (1) rather large deletions affecting one or more exons; (2) smaller deletions or insertions which result in a shift in the reading frame, leading to altered peptide sequence and/or truncation of proteins; (3) nonsense mutations resulting in truncated proteins; (4) three-nucleotide changes causing single codon deletions or insertions; (5) single nucleotide changes causing amino acid substitutions; and (6) a splice site mutation resulting in deletion of 94 amino acids and 3 TMDs.

The larger deletions and frameshift and nonsense mutations are obviously deleterious for MCT8 function. The functional consequences of single amino acid substitutions, deletions, or insertions have been investigated in cells transfected with wild-type or mutated MCT8. Most mutations were found to result in an almost complete loss of thyroid hormone transport by MCT8. However, the extent to which these mutations affect MCT8 function depends on the cell type used for functional studies, for reasons which need to be fully explored.133–136

Animal Models

Studies in humans and animals have indicated that MCT8 is expressed in a variety of tissues, including brain, liver, kidney, heart, skeletal muscle, and thyroid. The distribution of MCT8 expression in mouse brain has been examined in detail by Heuer et al.,¹³⁷ indicating that MCT8 is predominantly found in neurons in different brain areas, including hippocampus, cerebral cortex, striatum, hypothalamus, and cerebellum. Significantly, MCT8 is also expressed in capillary endothelial cells, the choroid plexus, and tanycytes which line the third ventricle.^137,138 MCT8 expression in neurons coincides with expression of DIO3, which catalyzes the degradation of T₃. DIO2, which catalyzes the conversion of T₄ to T₃, is largely expressed in adjacent astrocytes. Another transporter involved specifically in brain T₄ uptake, OATP1C1, is expressed in capillaries and the choroid plexus.^137,138

Based on studies by Heuer et al.¹³⁷and Bernal,¹³⁹ a pathway which regulates T₃ supply to neuronal target cells is shown in Fig. 23-6. The steps involved in this process include: (1) transport of T₄ by OATP1C1 through the blood-brain barrier, (2) uptake of T₄ into astrocytes by an unidentified transporter, (3) conversion of T₄ to T₃ by DIO2 in astrocytes, (4) release of T₃ from the astrocytes by another unidentified transporter, and (5) neuronal uptake of T₃ mediated by MCT8. Neurons may also express DIO3 to catabolize and terminate T₃ action, but this schema is an oversimplification. It ignores the importance of thyroid hormone transport across the blood-brain barrier by MCT8 and across the blood-CSF barrier by both MCT8 and OATP1C1, as well as the importance of other target cells for thyroid hormone in the brain, such as oligodendrocytes.

MCT8 KO mice have been studied by Trajkovic et al.,¹⁴⁰ Dumitrescu et al.,¹⁴¹ and Wirth et al.¹⁴² In contrast to the severe neurologic features in male patients with MCT8 mutations, neither hemizygous MCT8 null male mice nor homozygous MCT8 KO female mice show an obvious neurologic phenotype. However, they do exhibit the same biochemical thyroid abnormalities as patients with MCT8 mutations: a large decrease in T₄, a large increase in serum T₃, and slightly elevated TSH levels. In addition, MCT8 KO mice show the following features: (1) normal brain T₄ uptake but impaired brain T₃ uptake, (2) decreased brain T₄ and T₃ content, (3) increased DIO2 and decreased DIO3 activities in brain, (4) normal liver T₄ and T₃ uptake, (5) increased kidney T₄ and T₃ uptake, (6) increased kidney T₄ and T₃ content, and (7) increased type 1 deiodinase (DIO1) activity in both liver and kidney.

The paradoxical increase in renal T₄ and T₃ uptake in MCT8 KO mice is unexplained, but the combination of increased renal T₄ content and DIO1 expression may lead to enhanced renal T₄-to-T₃ conversion, thus contributing to the observed decrease in serum T₄ and increase in serum T₃ levels.¹⁴³ There is also evidence suggesting that thyroidal hormone synthesis is affected by MCT8 inactivation, leading to preferential T₃ secretion (Trajkovic et al., unpublished observations). Since MCT8 is expressed in the hypothalamus, its inactivation is associated with impaired feedback action of thyroid hormone, presumably contributing to slightly increased serum TSH levels.¹⁴⁰ The lack of an obvious neurologic phenotype in MCT8 KO mice remains to be explained.

Pathogenesis

The known essential role of thyroid hormone in brain development requires optimal spatiotemporal regulation of T₃ supply to CNS target cells, and MCT8 is critical for T₃ transport into central neurons. Inactivation of MCT8 and neuronal T₃ deprivation results in impaired CNS development, leading to severe psychomotor retardation. It is also conceivable that MCT8 is more important for T₃ uptake in a subset of neurons, resulting in an imbalance of T₃ supply to different neuronal populations and defective coordinated development of neuronal networks in the brain.

Depending on the importance of MCT8 for T₃ transport across the blood-brain barrier and choroid plexus, MCT8 inactivation may also result in an overall reduction in brain T₃ uptake, as seen in MCT8 KO mice. It is also possible that the abnormal circulating T₄ and T₃ levels in MCT8 deficiency are directly detrimental for brain development. Elucidation of pathogenic mechanisms responsible for psychomotor retardation may have important implications for the management of patients with MCT8 mutations.

In addition to dysregulated thyroid hormone action in the brain, the effects of MCT8 mutations on the thyroid status of peripheral tissues should also be considered. Despite exposure to highly elevated circulating T₃ levels, the heart usually appears to function normally in MCT8 patients, suggesting partially impaired cardiac T₃ uptake and implying the involvement of additional thyroid hormone transporters in the heart. MCT8 patients exhibit profound muscle wasting and increased serum SHBG levels, which likely reflect a hyperthyroid state of skeletal muscles and liver, respectively. This indicates that MCT8 inactivation does not impair muscle and liver T₃ uptake and suggests that other transporters may be more important in these tissues. Finally, findings in MCT8 KO mice also suggest renal hyperthyroidism in MCT8 patients, but there is no direct clinical evidence to support this notion.

Management

Two types of treatment have been evaluated in MCT8 deficiency. One is normalization of serum T₄ and T₃ levels with a block-and-replace regimen using a combination of PTU and T₄. Treatment of a 16-year-old boy with markedly low body mass (25 kg) and tachycardia did not result in major neurologic improvement but had a marked beneficial effect on body weight and heart rate.¹⁴⁴ Perhaps neurologic benefit can only occur if such therapy is initiated soon after birth.

An alternative treatment could involve the administration of a thyroid hormone analog that is taken up by the brain independently of MCT8. Promising results using diiodothyropropionic acid (DITPA)¹⁴⁵ have been observed in MCT8 KO mice. Clinical trials in patients with MCT8 mutations have been initiated, and the results are eagerly awaited.

Clinical Features

Three families (A, B, C) with affected individuals exhibiting a disorder of thyroid hormone metabolism have been described.^146,147 In each instance, childhood growth retardation was a common feature that brought probands to clinical attention. Affected individuals showed a distinctive abnormal pattern of thyroid function tests, with elevated free T₄, low free T₃, raised reverse T₃, and normal or slightly high TSH levels. This pattern was suggestive of a defect in iodothyronine metabolism. Consistent with this hypothesis, affected siblings in family A required higher-than-normal amounts of exogenous T₄ to suppress TSH levels, whereas their response to T₃ administration was normal.¹⁴⁶ We have identified additional adult and childhood cases of this disorder with a similar pattern of thyroid function tests and growth retardation in childhood (Gurnell, Beck-Peccoz, and Chatterjee, unpublished observations).

Molecular Genetics

The biochemical phenotype in affected cases suggested a defect in T₄-to-T₃ conversion, but linkage studies ruled out defects at DIO loci or in genes involved in posttranslational modification (ubiquitination/de-ubiquitination) of DIO2. However, affected subjects in family A shared homozygous haplotypes at the SECISBP2/SBP2 locus.¹⁴⁶ Subsequent analyses of this gene have identified a homozygous missense mutation (R540Q) in cases from family A, compound heterozygous abnormalities (nonsense mutation K438X plus missplicing of ~50% of transcripts from the other allele) in the proband from family B, and a homozygous stop mutation (R128X) in the propositus from family C.¹⁴⁷

There are 25 known human proteins which contain the amino acid selenocysteine (Sec), and SECIS-binding protein 2 (SBP2) is a factor required for the cotranslational incorporation of Sec during their biosynthesis. The mechanism of selenoprotein synthesis and role of SBP2 is further described in Fig 23-7. Recent studies also indicate that the architecture of SBP2 is complex, with alternative splicing of the gene generating multiple transcripts and internal methionine residues directing synthesis of shorter protein isoforms.¹⁴⁸ Indeed, there is evidence (albeit in vitro) to suggest that usage of methionines downstream of a homozygous null mutation (e.g., in proband of family C) might generate shorter but functional SBP2 protein to ameliorate the phenotype of this disorder.¹⁴⁷

Pathogenesis

Selenocysteine is a component of all three deiodinase enzymes, and DIO2 activity was indeed reduced in fibroblasts from family A.¹⁴⁶ However, based on the biochemical phenotype of DIO null mice, it is likely that the abnormal thyroid function test pattern in this disorder is likely to be mediated by combined, partial deficiency of all three DIOs rather than lack of a single enzyme.

Targeted disruption of the murine SBP2 gene has not been described, so no animal model of this disorder exists, but cellular knockdown of SBP2 has been achieved and is associated with variable but global reduction in levels of many selenoproteins.¹⁴⁹ Consistent with this notion, deficiencies of other selenoproteins have been documented in affected cases: glutathione peroxidase (GPx) activity in cells (mainly GPx type1) and serum (mainly GPx type 3) is markedly reduced, and circulating levels of hepatic selenoprotein P (SEPP) are low.^146,147 Such deficiency of the major circulating selenoproteins (SEPP, GPx3) is also likely to be the basis of low serum selenium levels recorded in cases.¹⁴⁶ Furthermore, functional characterization of the mutant SBP2 protein identified in family A indicates that its ability to bind Sec insertion sequence (SECIS) elements in other selenoprotein genes (e.g., GPx4) is impaired,¹⁵⁰ suggesting the possibility of more widespread selenoprotein deficiencies in patients with this disorder.

Management

Trials of oral selenium supplementation, either in the form of selenomethionine-rich yeast which can be incorporated generally into circulating proteins or sodium selenite, a substrate for selenocysteine incorporation, have been undertaken in affected cases. Although selenomethionine treatment raised circulating selenium concentrations, there was no change in thyroid function, GPx3 activity or SEPP levels.^147,151 However, T₃ treatment was clearly beneficial for growth in one published report¹⁴⁷ and our childhood case (Gurnell and Chatterjee, unpublished observations).

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