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EXPERIENCE & REASON |
a Third Department of Pediatrics, University of Athens School of Medicine, Attikon University Hospital, Athens, Greece
b Departments of Medicine
d Pediatrics
e Committees on Genetics and Molecular Medicine, and J.P. Kennedy Mental Retardation and Developmental Disabilities Center, University of Chicago, Chicago, Illinois
c Neurology Department, Penteli Children's Hospital, Athens, Greece
ABSTRACT
Monocarboxylate transporter 8 acts as a specific cell membrane transporter for thyroxine and especially triiodothyronine into target cells. It is expressed in brain neurons and in many other tissues. The monocarboxylate transporter 8 gene resides on chromosome Xq13.2. An 11-month-old male infant was referred because of severe hypotonia from early life and global developmental delay. Thyroid-function tests showed normal thyrotropin levels and the characteristic for the disorder, including high serum triiodothyronine and low thyroxine concentrations. Molecular analysis of the monocarboxylate transporter 8 gene showed that the patient was hemizygous for a novel missense mutation P537L. This case highlights the importance of determining thyroid hormone levels, especially triiodothyronine, in infants with severe neonatal hypotonia.
Key Words: monocarboxylate transporter 8 • neonatal hypotonia • developmental delay • thyroid hormones
Abbreviations: TH—thyroid hormone • CNS—central nervous system • T3—3,3',5-triiodothyronine • D1—type 1 5'-deiodinase • D2—type 2 5'-deiodinase • T4—thyroxine • rT3—3,3',5'-triiododothyronine • MCT8—monocarboxylate transporter 8 • TFT—thyroid-function test • L-T4—L-thyroxine
Thyroid hormone (TH) is crucial for the maturation and function of the central nervous system (CNS). TH also exerts a broad range of effects on growth, metabolism, and physiologic function of virtually all tissues.1 Most TH effects are mediated by specific TH receptors, which modulate the level of transcription of target genes. Some effects take place in the cytoplasm and are broadly known as nongenomic.2 TH is synthesized and secreted from the thyroid gland mainly as the prohormone thyroxine (T4). The principal bioactive form of TH, 3,3',5-triiodothyronine (T3), is produced in virtually all tissues by outer ring deiodination of thyroxine, a reaction catalyzed by type 1 and type 2 5'-deiodinases (D1 and D2, respectively). D1 is found in peripheral tissues, such as the liver, kidney, and thyroid, and is responsible for the conversion of the majority of thyroxine to T3 in the circulation. D2 is found in the brain, pituitary, thyroid, and skeletal muscle. Thus, D2 has the important function to provide T3 to the brain and pituitary.3 Type 3 5-deiodinase converts T4 to the inactive metabolite 3,3',5'-triiododothyronine (rT3) and T3 to 3,3'-diiodothyronine by inner ring deiodination.4 Type 3 5-deiodinase is expressed in the brain, especially during fetal development, as well as in other fetal tissues, the placenta, and the pregnant uterus. For both genomic and nongenomic mechanisms of action, TH has to cross the cell membrane. This passage into the cell is facilitated by specific transport proteins, several of which have been identified recently.5
Monocarboxylate transporter 8 (MCT8) acts as a specific transporter of T4 and especially for T3.6 The gene for MCT8 resides on chromosome Xq13.2. MCT8 is expressed in brain neurons and other tissues, for example, muscle, bone, and liver. Mutations of the MCT8 gene have only recently been identified; they result in severe psychomotor retardation and abnormal thyroid-function tests (TFTs) that are characterized by a high serum total and free T3 and low total and free T4, as well as low rT3.7
CASE REPORT
An 11-month-old boy was referred because of severe hypotonia from early life and global developmental delay. He was born after an uncomplicated term pregnancy with a birth weight of 2.5 kg. His parents were not consanguineous. No perinatal distress was reported, but he was noted to have a weak cry. At presentation his body length was 77 cm (
80th percentile), weight was 8.1 kg (10th percentile), and head circumference was 46 cm (55th percentile). He exhibited severe generalized hypotonia and decreased muscle strength, hyperactive deep tendon reflexes, and severe head lag and was unable to sit independently. He showed no signs of thyroid dysfunction, and the thyroid was nonpalpable. His cardiovascular examination was normal. Neonatal thyroid screening by measurement of thyrotropin was within the reference range (ie, spot thyrotropin <25 µIU/mL). Biochemical investigation included serum glucose, serum urea nitrogen, serum creatinine, K+, Na+, Cl–, Ca+2, phosphorus, alkaline phosphatase, Mg+2, aspartate aminotransferase, alanine aminotransferase, 
-glutamyl transpeptidase, lactate dehydrogenase, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, lactate, and total protein, all of which were within the reference ranges except for a mildly elevated lactate level of 23.9 mg/dL (reference: <20 mg/dL). At 11 months of age, the serum total and free T3 levels were high, T4 was low, and thyrotropin was within the reference range (Table 1). A brain MRI showed decreased myelination of the subcortical tissue and thalamus. Clinical presentation, biochemical profile (high T3 and low T4), brain MRI, and the gender of the patient suggested the possibility of an MCT8 gene mutation. Family history was also suggestive of an X-linked disorder (Fig 1). His maternal uncle presented an unidentified neurologic disorder preceding death at the age of 8 years. The patient had 3 brothers, 2 of them without a neurologic disorder; however, the third one had presented muscular hypotonia since birth and died at the age of 9 months from aspiration pneumonia. Molecular analysis of the MCT8 gene of the family (Fig 1) showed that the patient and his mother, maternal aunt, and grandmother carried a point mutation, a single nucleotide substitution (cytosine to thymidine) in exon 5, which results in the replacement of the normal proline 537 with a leucine. This mutation, P537L, has not been reported previously. L-thyroxine (L-T4) administration (37.5 µg/day) resulted at 13 months (Table 1) in the restoration of a normal free T4 level of 1.1 ng/dL, a further increase in the free T3 level to 8.5 pg/mL, and a suppressed thyrotropin level of 0.19 µIU/mL but did not improve the patient's neurologic condition. The TFTs at 18 months while on 25 µg of L-T4 daily (Table 1 and Fig 1) showed an increased total T3 concentration of 280 ng/dL with a normal T4 level of 8.3 µg/dL and a normal rT3 level of 19.9 ng/dL, likely because of normalization of the circulating T4 level. TFTs of the 3 heterozygous female carriers and 3 unaffected family members were within the reference range (Fig 1). However, serum T3 concentrations in the carrier females tended to be higher and those of rT3 lower relative to the unaffected family members. More specifically, the T3 level was 181, 155, and 182 ng/dL in the heterozygotes compared with 125, 167, and 119 ng/dL in the unaffected. Similarly, the rT3 level was 20.9, 15.5, and 16.1 ng/dL in the heterozygotes compared with 20.9, 27.8, and 32.5 ng/dL in the unaffected subjects (Fig 1). This trend of intermediate values in heterozygous females, though noted previously, and its physiologic mechanism confirmed7,8 has no diagnostic value in predicting the carrier state of individual subjects.
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DISCUSSION
Loss-of-function mutations of the MCT8 gene result in a dramatic reduction in T3 uptake by the brain neurons, cerebral hypothyroidism, and a neurologic phenotype of profound hypotonia and developmental delay, described in this and other patients.7,9–14 Evidence for the importance of MCT8 on brain function in humans became evident with the identification of the MCT8 gene mutations in 2 boys with neuropsychiatric defects and elevated serum T3 levels.7 This was followed by the publication describing 5 more unrelated boys9 and, ultimately, the realization that patients with Allan-Herndon-Dudley syndrome also carry a mutation in the MCT8 gene.10 This syndrome was among the first X-linked mental retardation syndromes to be clinically described. Based on >100 subjects, the clinical manifestations are now well defined. In infancy and childhood, the characteristics are marked hypotonia, weakness, generalized muscular atrophy, and delay of developmental milestones. Head circumference is normal; however, a number of patients present acquired microcephaly usually manifesting after the seventh month of life. Other neurologic manifestations include spastic paraplegia with hyperreflexia, clonus, and Babinski reflexes. In adult life, hypotonia turns to spasticity. Cognitive development is severely impaired.11 MCT8 deficiency has been also associated with X-linked paroxysmal dyskinesia and progressive atrophy of the cerebrum, basal ganglia, and midbrain.15
The recent development of animal models of MCT8 deficiency8,16 has helped in unraveling the pathophysiologic mechanism that gives rise to the abnormal TFTs. The reduced entry of T4 into brain cells stimulates D2 activity, whereas excess of TH in liver, reflecting cellular uptake of serum T3 through transporters different from MCT8, stimulates D1 activity. This results in the formation of more T3 and consumption of T4. The reduced uptake of T3 further enhances T3 accumulation in serum. The low rT3 levels are explained by the increased rT3 metabolism because of increased D1 activity and the consumption of T4. The role of MCT8 on the CNS is less well understood. It is likely that MCT8 deficiency results in the reduction of T3 uptake by brain neurons producing early CNS hypothyroidism in the embryo resulting in hypotonia and global developmental delay. However, the possibility that MCT8 could transport yet another substrate, vital to CNS function, has not been excluded.
In our patient, thyrotropin suppression and normal rT3 levels when serum T4 were normalized, while on L-T4 treatment, suggest a more limited role of MCT8 on T4 transport into the pituitary thyrotrophs. The increased serum lactate levels are compatible with the concept of peripheral thyrotoxicosis.
Whether tests used for neonatal screening of hypothyroidism could detect MCT8 defects is not known, because this condition was not recognized until very recently.7,9 Retrospective review showed that thyrotropin measurements had been within the reference range at birth.7,14,17 This is not surprising given the broad reference range at birth and that only a small number of the affected individuals manifest later minimal increases in thyrotropin.7,9 In contrast, blood T4 was low at the neonatal screen in both subjects in whom this test was reported.7,17 However, because the T4 concentration is often low in neonates because of reduced serum T4 binding, this common trivial finding has led most screening programs to abandon T4 testing in favor of thyrotropin. T3 values are normally very low at birth and rise rapidly in the first few days of life. High neonatal T3 values may be of diagnostic value for MCT8 defects, but the precise timing of sampling and prematurity could be seriously confounding.
Currently the best method for early diagnosis is to obtain TFTs in infants with hypotonia and feeding difficulties, which should be evident to the astute pediatrician by the second week of life. An earlier diagnosis or even prenatal testing should be reserved for infants born to mothers known to be heterozygous for an MCT8 gene mutation.
Most vexing is the failure of affected individuals to respond to TH treatment, even when given at an early age. Development of TH analogs that enter brain cells by alternative routes to MCT8 are in progress. Currently, prenatal testing and genetic counseling of carrier women can prevent the transmission of this defect to male offspring.
CONCLUSIONS
MCT8 mutations result in severe neonatal hypotonia and global developmental delay. Moreover, this case highlights the importance of determining TH levels, especially T3, in patients with early postnatal hypotonia.
ACKNOWLEDGMENTS
This work was supported by National Institutes of Health grants DK15070 and RR00055.
FOOTNOTES
Accepted May 24, 2007.
Address correspondence to Anastasios Papadimitriou, MD, Pediatric Endocrinology Unit, Third Department of Pediatrics, University of Athens School of Medicine, Attikon University Hospital, Rimini 1, Haidari, Athens 124 62, Greece. E-mail: anpapad{at}med.uoa.gr
The authors have indicated they have no financial relationships relevant to this article to disclose.
REFERENCES
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