THE PRESENTATION OF A NOVEL SYNDROME CAUSED BY MUTATIONS IN THE - - PDF document

THE PRESENTATION OF A NOVEL SYNDROME CAUSED BY MUTATIONS IN THE X-LINKED THYROID HORMONE TRANSPORTER, MCT8#

Alexandra M. Dumitrescu1,*, S. Refetoff2

1 M.D, Ph.D, Postdoctoral Scholar, Department of Medicine University of Chicago 2 M.D, Professor of Medicine, Pediatrics, Molecular Medicine and Genetics, University of

Chicago

INTRODUCTION

The effects of thyroid hormone (TH) are dependent on the quantity of the hormone that reaches peripheral tissues, its intracellular availability and the presence of unaltered TH receptors (TR). Until recently it was believed that TH enters the cells passively. However, the characterization of several classes of TH membrane transporters with different kinetics and substrate preferences that actively transport TH across cell membranes has changed this paradigm. These proteins belong to different families of solute carriers, organic anions (OATP), amino acids, and monocarboxylate transporters (1-5). Their characteristics in terms of tissue distribution and kinetics, as well as binding

• f other possible ligands, provide them with potentially distinctive roles in the fine

tuning of organ-specific TH availability (6). Once intracellularly, the hormone precursor thyroxine (T4) is metabolized by removal of the outer ring iodine (5’-deiodination) to form triiodothyronine (T3) or, inactivate T4 and T3 by inner ring, 5-deiodination to form reverse T3 (rT3) and T2,

• respectively. The activating deiodinases are D1 and D2, while the inactivating enzyme

is D3 and to a lesser extent D1 (Fig. 1). Their presence in changing concentrations in various cell types allows an additional level of local regulation of hormone supply (7). Finally, the presence and abundance of TRs, through which TH action is mediated, determine the type and degree of hormonal response (8). Since the identification of TH membrane transporters, their physiological role has remained elusive as no genetic defects were known in humans or animals, and the consequence of a putative defect

69

Editorial

Acta Endocrinologica (Buc), vol. III, no. 1, p. 69 - 80, 2007 *Correspondence to: Alexandra M. Dumitrescu, M.D. Ph.D., Postdoctoral Scholar, Department of Medicine University of Chicago, 5841 S. Maryland Avenue, MC3090, Room M367, Chicago, IL 60615, Phone: 773-702-9273, Fax: 773-702-6940, Email: alexd@uchicago.edu # Partially reproduced from Dumitrescu, AM and Refetoff, S: Conditions with Variable Effects: Cell Transport Defects. In Clinical Management of Thyroid Diseases, Wondisford, F and Radovick, S (eds.), Elsevier, Philadelphia, PA and Amsterdam, the Netherlands, 2007, with permission.

was unknown. In particular, a defect in liver specific transporter (LST) 1 was considered as a possible cause of resistance to TH (RTH). Linkage analysis in several families with RTH has excluded LST1 involvement (9). However, the recent identification of patients with mutations in the X-linked TH transporter, monocarboxylate transporter 8 (MCT8) (10-16), has revealed the role played by one such transmembrane carrier in the intracellular availability of TH. Being an X-linked disease, hemizygous males are affected while the carrier females are clinically normal. The phenotype of patients with MCT8 gene mutations has two components 1) thyroid function tests (TFT) abnormalities that include high T3, low T4, low rT3 and slightly elevated TSH (Fig. 2) found in both males and to a lesser degree in carrier females and 2) severe motor and developmental delay, gait disturbance, dystonia, and poor head control, found only in males. These neuropsychiatric manifestations have not been previously described in the context

• f abnormal thyroid function and cannot be explained by the current knowledge and

the observed TFT. This is the first genetic defect of a TH transporter and understanding the underlying mechanisms responsible for the phenotype manifested by patients with MCT8 defect will provide new insights into thyroid physiology.

Alexandra Dumitrescu and S. Refetoff 70 Figure 1. Regulation of intracellular TH bioactivity. TH, T4 and T3, are actively transported across the cell membrane. T4, the main hormonal precursor secreted by the thyroid gland, undergoes intracellular stepwise deiodination. 5'-deiodination through D1 and D2 activates T4 by converting it to T3, while 5-deiodination by D3 converts T4 to the inactive rT3. T3 is inactivated by D3 and, to a lesser extent, by D1.

EPIDEMIOLOGY, ETIOLOGY AND PATHOGENESIS

The MCT8 gene was first cloned during the physical characterization of the Xq13.2 region known to contain the X-inactivation center (17). It has 6 exons and a very long (more than 100kb) first intron. It belongs to a family of genes, officially named SLC16, the products of which catalyze proton-linked transport of monocarboxylates, such as lactate, pyruvate and ketone bodies. The deduced products of the MCT8 (SLC16A2) gene are proteins of 613 and 539 amino acids (translated from two in-frame start sites) containing 12 transmembrane domains with both amino- and carboxyl- termini located within the cell (18). In 2003, Friesema et al (2) demonstrated that the rat homologue was a specific transporter of TH into cells. A form of mental retardation associated with motor abnormalities was described in 1944 (19) and subsequently named the Allan-Herndon-Dudley (A-H- D) syndrome. This condition was further mapped to a locus on chromosome X: Xq13-q21 (20) and Xq12-q13 (21). In 2004, two laboratories identified independently mutations in the MCT8 gene in 7 unrelated families, in which males presented with high serum T3, low T4 and low rT3 concentrations together with psychomotor abnormalities reminiscent of the A-H-D syndrome (10, 11). The following year it was shown that families previously identified as suffering from the A-H-D syndrome, including the first family reported in 1944, harbored mutations

Thyroid hormone transporter MCT8 mutations 71 Figure 2. Thyroid function tests from six families studied at the University of Chicago: seven affected males (M), eleven carrier females (F), and fifteen unaffected family members (N). (* P <0.05; ** P<0.01, *** P<0.001). Shaded area depicts the normal range for the corresponding test. Bars represent 2 SDs.

in the MCT8 gene and had high serum T3 levels (12). We know of 26 families with MCT8 gene mutations (14, 22) (and personal

• bservations). The mutations are distributed throughout the coding region of the

gene (Fig. 3) Single amino acid substitutions causing missense mutations were found in 10 families and in 4 families they resulted in nonsense mutations. Single amino acid deletions or insertions were reported in two families each. One or two nucleotide deletions or insertions produced 2 stop codons and in one case a 64 amino acid extension of the carboxyl terminus of the MCT8 molecule. Deletions of 10 nucleotides or more were reported in four families, and an intronic mutation, affecting the splice site, in one. It is of note that two mutations, F229∆ and S448X,

• ccurred in two unrelated families each.

The identification of 26 families with MCT8 defect in less than three years indicates that this syndrome is more common than initially suspected. From a population genetics point of view, the spontaneous MCT8 mutations could have been maintained in the population since carrier females are asymptomatic, thus preventing any negative selection to take place. Currently, penetrance is thought to be complete. Ethnic origins reported to date include German, Greek, Amerindian, English, Irish, French, Japanese, Hispanic, Brazilian, Argentinean, Chilean, Mexican and Dutch. Genotype/Phenotype Correlation Given the variability in the severity of the disease for correlations between phenotypes and genotypes were sought. A comparison of the clinical picture in the families with identical mutations would have been helpful in determining if such correlations exist. Unfortunately, detailed clinical information in one of each of the

Alexandra Dumitrescu and S. Refetoff 72 Figure 3. Schematic representation of MCT8 gene mutations in 26 families. Their type and location are presented graphically. (M, missense; X, nonsense; I, insertion; D, deletion).

two families is not available. However, early deaths were reported in the two families with a truncated MCT8 molecule (S448X). In one family two affected males died at ages 13 and 39 years, and in the other, deaths occurred at 20, 22, and 30 years. Early death also was reported in subjects harboring the following mutations: P537L, 404 frameshift 416X, F229∆, S194F, and 612 frameshift with 64 amino acid carboxyl-terminal extension. The cause of death in 4 of 14 was aspiration pneumonia. Prediction of outcome based on the genotype would help in the care of patients and in genetic counseling. Cultured skin fibroblasts from males with MCT8 deficiency [L512P and delAFrSh404(416X)] showed a significant reduction T4 and T3 uptake (23). It was,

• n average, 24% and 7.3%, respectively, compared to 100% in fibroblasts from

normal individuals. Baseline D2 enzymatic activity was 6 to 8-fold higher. Fibroblasts from carrier females gave results intermediate to those of affected males and normals. Cellular T3 uptake of WT MCT8 and 12 different mutant MCT8 proteins was examined in JEG3 cells transfected with the respective constructs (22) and revealed no activity in 4 mutations, 2 missense (Leu471Pro and Leu512Pro) and 2 nonsense mutations (Arg245X and Ser448X). In 3 mutations, (F229Ä, insertion Ile189 and Ala224Val), uptake was from 2.4 to 5%. In the remaining 5 mutations, T3 uptake ranged from 8.6 to 33% that of the wild-type MCT8; all five were missense mutations (S194F, V235M, R271H, L434W, and L598P). Using available clinical, chemical and in vitro information, there is no clear relation between the degree of impairment of T3 transport by the mutant MCT8 molecules and the level of serum T3. This is probably due to the important role played by the underlying perturbations in the metabolism of iodothyronines in the production

• f T3 as demonstrated in the Mct8 knockout mice (24). Furthermore, except for early

death, no other clinical consequence appears to significantly correlate with the degree

• f functional or physical disruption of the MCT8 molecule. Genetic factors,

variability of tissue expression of MCT8, and other iodothyronine cell membrane transporters could be at the basis of this lack of phenotype/genotype correlation. However, the possibility that MCT8 is involved in the transport of other ligands has not been excluded. Mouse Model of the Disease To better understand the mechanism underlying the phenotype of MCT8 deficiency, mice lacking functional Mct8 were created by homologous recombination (24). These mice replicate the characteristic thyroid phenotype observed in humans: high serum T3, low T4 and rT3 compared to wild-type (WT) male littermates (24). Thus, Mct8 knockout (KO) mice are a good model for the study of the pathophysiology underlying the thyroid phenotype. Studies of Mct8KO (24) have provided much needed insights into the mechanisms responsible for the thyroid phenotype (25). Measurements of tissue T3 content demonstrated that the high circulating T3 levels are differentially available to tissues, depending on the redundancy in TH transmembrane transporters. Tissues that

Thyroid hormone transporter MCT8 mutations 73

express other transporters besides Mct8, such as the liver (26), manifest hormonal responses that reflect the circulating T3 levels and are, thus, thyrotoxic in Mct8 deficient mice (Fig. 4A). The baseline hepatic thyrotoxicosis in Mct8KO mice results in increased D1 enzymatic activity (Fig. 4B), decreased serum cholesterol and increased alkaline phosphatase (Fig. 4C). In contrast, tissues with limited redundancy in cellular TH transporters, such as the brain (26), have decreased T3 content in Mct8KO mice (Fig. 4D). As a consequence, the local D2 enzymatic activity is increased (Fig. 4E). The role of D2 is to maintain local levels of T3 in the context of TH deficiency and its activity is post-translational regulated by TH availability (7).

Alexandra Dumitrescu and S. Refetoff 74 Figure 4. Consequences of Mct8 deficiency: (A) Liver T3 content; (B) Liver deiodinase 1 enzymatic activity; (C) Serum cholesterol and alkaline phosphatase levels; (D) Brain T3 content; (E) Brain deiodinase 2 enzymatic activity. Bars represent mean SD. (WT, male wild type mice; Mct8-/y, male Mct8 knockout mice; S.A., specific activity; (* P <0.05; ** P<0.01, *** P<0.001).

The findings of coexistent TH excess and deficiency in Mct8 KO mice can explain, in part, the mechanisms responsible for the pattern of thyroid tests observed in MCT8 deficiency (24). The increased D1 and D2 activity, stimulated by opposite states of intracellular TH availability, has an additive consumptive effect on T4 levels and results in increased T3 generation. The impaired T3 uptake in the brain makes the circulating T3 less available for deiodination by D3. The increased liver D1 enzymatic activity also stimulates the metabolism of rT3. In addition, these tissue specific differences in intracellular TH content and consecutive changes in TH metabolism are responsible for the unusual clinical presentation of this defect compared to global TH deficiency.

CLINICAL FEATURES

Male patients that are found to have MCT8 mutations are referred for medical investigation during infancy or early childhood because of neurodevelopmental

• abnormalities. They present with hypotonia, motor delay, feeding problems, inability

to walk and no speech development (Fig. 5). The clinical presentation of more than 100 male patients with MCT8 gene mutations known to date is very similar, with consistent TFT abnormalities, described earlier, and severe psychomotor retardation. Review of these families indicates that parents were not consanguineous and gestation and delivery were normal. Infants were normal in length, weight, and head circumference. They do not show typical signs of hypothyroidism such as prolonged neonatal jaundice, macroglossia, umbilical hernia, or signs of hyperthyroidism, increased heart rate and premature closure of the fontanelles. An early sign of the defect, manifesting in the first few weeks of life, was hypotonia and feeding difficulties.

Thyroid hormone transporter MCT8 mutations 75 Figure 5 Picture of a 5-year old with MCT8 gene mutation. The child cannot talk, cannot walk and cannot feed himself. He has spastic quadriplegia and has to be propped and supported in a sitting position.

With advancing age, weight gain lagged behind normal and microcephaly became apparent, while linear growth proceeded normally. Although truncal hypotonia persisted, there was progressive development of limb rigidity leading to spastic quadriplegia, often with joint contractures. In these cases muscle mass is diminished with generalized muscle weakness, often with myopathic facies but characteristic poor head control, originally described as “limber neck” (19). Purposeless movements in the form of choreoathetosis and characteristic paroxysms of kinesigenic dyskinesias are

• common. These are typically triggered by somatosensory stimuli, such as changing of

clothes or lifting the child. The attacks consist of extension of the body, opening of the mouth, and stretching or flexing of the limbs lasting less than minutes (27). In addition to these nonepileptic events, true seizures can also occur. Reflexes are usually brisk, clonus is often present but nystagmus and extension plantar responses are less

• common. Most affected children are never able to sit by themselves or walk; those that

manage to do so, lose this ability with time, indicating progressive deterioration. Cognitive impairment is severe. Individuals never develop speech or, at the most, acquire the ability to emit garbled sounds. Their behavior tends to be passive with little evidence of aggressiveness and they appear to respond to their surroundings by a social

• smile. Although brain MRIs are often normal, atrophy of the cerebrum, thalamus, and

basal ganglia have been reported, probably reflecting dysmyelination (14, 15). Female carriers do not manifest any of the above described psychomotor abnormalities. However, intellectual delay and frank mental retardation have been described (10, 16).

DIAGNOSIS

Most characteristic, if not pathognomonic, is the high serum T3 and low rT3

• concentrations. Although T4 is reduced in most cases and is usually the first thyroid

abnormality identified during neonatal screening, T4 has been normal in some individuals (13). TSH levels are normal or slightly elevated, rarely above 6mU/L. It is of interest that heterozygous female carriers have serum TH concentrations intermediate between affected males and unaffected family members (Fig 2). Yet, they lack the typical psychomotor abnormalities always found in the affected males. Current diagnostic criteria include: the characteristic thyroid abnormalities accompanied by truncal hypotonia, limb spasticity, poor head control, motor delays and absent speech. The definitive diagnosis is made by the identification of mutations in the MCT8 gene. Our experience has been that the TFT are very specifically associated with MCT8 defect. Sequencing of the MCT8 gene in males with similar neuropsychiatric manifestations but who do not present the pathognomic TFT abnormalities has given negative results. The TFT pattern with high T3, low T4 and low rT3, though characteristic of MCT8 deficiency could be the consequence of other defects causing TH metabolism abnormalities. However, no genetic defects in deiodinases have been so far identified in humans. All three deiodinase genes were initial candidate genes in

Alexandra Dumitrescu and S. Refetoff 76

MCT8 and other defects with abnormal ratios of active and inactive TH (28). They were eventually excluded by sequence and linkage analysis. Work from Mct8 KO mice has demonstrated secondary defects in TH metabolism due to the tissue specific TH availability and to the intrinsic complex regulation of deiodinases. The high serum T3 levels with normal or slightly elevated TSH are compatible with RTH, but the low T4 and low rT3 levels exclude this diagnosis. Serum transport defects would have normal free TH levels whereas in MCT8 defect both total and free levels are proportionally abnormal. In iodine deficiency normal T3 levels could be found in the context of low T4, but treatments with iodine

• r T4 would normalize the TFT abnormalities.

CLINICAL COURSE, PREVENTION AND TREATMENT

The natural course of the disease caused by MCT8 gene mutations is characterized by the profound motor impairment and absent speech development. Virtually all affected males become wheelchair bound in adult life. Although some achieve delayed and unsteady independent ambulation, they are dependent on the family care or are institutionalized. In some families there is early death, most often the cause is aspiration pneumonia. There are also reports of patients living beyond 70 years of age. Finding treatment options for patients with MCT8 gene mutations is

• challenging. Detection of elevated TSH by neonatal screening has prompted L-T4

treatment in several patients, but physiological doses were not able to improve the

• utcome as the cellular uptake of TH is impaired in MCT8 dependent tissues.

Administration of pharmacological doses of L-T4 during pregnancy and the efficacy

• f several TH analogues, to bypass the molecular defect by using alternative

transporters, are avenues with therapeutic potential and are being tested in the Mct8 deficient mice. Prenatal testing and genetic counseling of carrier females can prevent the transmission of this defect to male offspring.

CONCLUSIONS AND CONTROVERSIES

• 1. As neonatal screening for hypothyroidism is based on the detection of

elevated blood TSH and/or low T4, newborn affected by the syndrome are likely to be missed until suspected on the basis of neuro-developmental findings.

• 2. As carrier females are asymptomatic, the presence of abnormality is not

suspected, and thus not tested, until the birth of the first affected male.

• 3. Aspiration pneumonia is a common cause of death.
• 4. Although seizures are not a constant feature of the syndrome, when
• ccurring, could be refractory to standard anticonvulsivants.

Thyroid hormone transporter MCT8 mutations 77

• 5. There is a debate whether the severe neuropsychiatric manifestations are due

to the abnormalities in TH transport or whether MCT8 is required for the transport

• f an important, but yet unidentified substance.
• 6. It is uncertain whether brain damage is already present in the embryo or

develops after birth. This is of great importance in the planning of therapy.

• 7. It is not known if low T4 precede the elevated T3 and whether TFT

abnormalities are always present at birth.

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