The monocarboxylate transporter 8 (MCT8) gene, located on chromosome Xq13.2, encodes a thyroid hormone transporter that is involved in triiodothyronine (T3) uptake into central neurons. MCT8 mutations cause an X-linked syndromic disorder known as Allan-Herndon-Dudley syndrome (AHDS) that is characterized by severe psychomotor delays, abnormal thyroid function, and hypomyelinated leukodystrophies. We identified 2 AHDS patients with developmental delays, truncal hypotonia, and spastic paraplegia. These patients presented with psychomotor retardation and characteristic thyroid function abnormalities, such as elevated T3 and low T4 levels. Direct MCT8 sequencing identified heterozygous mutations in each patient: p.I114N and p.A224V, respectively. Because it is difficult to suspect AHDS solely according to neurological features, thyroid function, including the T3 level, should be screened in male patients with X-linked mental retardation. Although the clinical features of hypothyroidism cannot be improved by only administering levothyroxine treatment, early diagnosis, management, and appropriate genetic counseling should be provided to at-risk families.

Keywords:
Allan-Herndon-Dudley syndrome, X-linked mental retardation, Monocarboxylate transporter 8, Thyroid hormone transporter
1.
Heuer H, Visser TJ: Minireview: pathophysiological importance of thyroid hormone transporters. Endocrinology 2009;150:1078-1083.
2.
Lafreniere RG, Carrel L, Willard HF: A novel transmembrane transporter encoded by the XPCT gene in Xq13.2. Hum Mol Genet 1994;3:1133-1139.
3.
Dumitrescu AM, Liao XH, Best TB, Brockmann K, Refetoff S: A novel syndrome combining thyroid and neurological abnormalities is associated with mutations in a monocarboxylate transporter gene. Am J Hum Genet 2004;74:168-175.
4.
Jansen J, Friesema EC, Kester MH, Milici C, Reeser M, Gruters A, Barrett TG, Mancilla EE, Svensson J, Wemeau JL, Busi da Silva Canalli MH, Lundgren J, McEntagart ME, Hopper N, Arts WF, Visser TJ: Functional analysis of monocarboxylate transporter 8 mutations identified in patients with X-linked psychomotor retardation and elevated serum triiodothyronine. J Clin Endocrinol Metab 2007;92:2378-2381.
5.
Yen PM: Physiological and molecular basis of thyroid hormone action. Physiol Rev 2001;81:1097-1142.
6.
Tata JR: How specific are nuclear ‘receptors' for thyroid hormones? Nature 1975;257:18-23.
7.
Hennemann G, Docter R, Friesema EC, de Jong M, Krenning EP, Visser TJ: Plasma membrane transport of thyroid hormones and its role in thyroid hormone metabolism and bioavailability. Endocr Rev 2001;22:451-476.
8.
Sugiyama D, Kusuhara H, Taniguchi H, Ishikawa S, Nozaki Y, Aburatani H, Sugiyama Y: Functional characterization of rat brain-specific organic anion transporter (Oatp14) at the blood-brain barrier: high affinity transporter for thyroxine. J Biol Chem 2003;278:43489-43495.
9.
Friesema EC, Docter R, Moerings EP, Verrey F, Krenning EP, Hennemann G, Visser TJ: Thyroid hormone transport by the heterodimeric human system L amino acid transporter. Endocrinology 2001;142:4339-4348.
10.
Calvo R, Obregon MJ, Ruiz de Ona C, Escobar del Rey F, Morreale de Escobar G: Congenital hypothyroidism, as studied in rats. Crucial role of maternal thyroxine but not of 3,5,3′-triiodothyronine in the protection of the fetal brain. J Clin Invest 1990;86:889-899.
11.
Visser WE, Friesema EC, Jansen J, Visser TJ: Thyroid hormone transport in and out of cells. Trends Endocrinol Metab 2008;19:50-56.
12.
Tonduti D, Vanderver A, Berardinelli A, Schmidt JL, Collins CD, Novara F, Genni AD, Mita A, Triulzi F, Brunstrom-Hernandez JE, Zuffardi O, Balottin U, Orcesi S: MCT8 deficiency: extrapyramidal symptoms and delayed myelination as prominent features. J Child Neurol 2013;28:795-800.
13.
Azzolini S, Nosadini M, Balzarin M, Sartori S, Suppiej A, Mardari R, Greggio NA, Toldo I: Delayed myelination is not a constant feature of Allan-Herndon-Dudley syndrome: report of a new case and review of the literature. Brain Dev 2014;36:716-720.
14.
Vaurs-Barriere C, Deville M, Sarret C, Giraud G, Des Portes V, Prats-Vinas JM, De Michele G, Dan B, Brady AF, Boespflug-Tanguy O, Touraine R: Pelizaeus-Merzbacher-Like disease presentation of MCT8 mutated male subjects. Ann Neurol 2009;65:114-118.
15.
Namba N, Etani Y, Kitaoka T, Nakamoto Y, Nakacho M, Bessho K, Miyoshi Y, Mushiake S, Mohri I, Arai H, Taniike M, Ozono K: Clinical phenotype and endocrinological investigations in a patient with a mutation in the MCT8 thyroid hormone transporter. Eur J Pediatr 2008;167:785-791.
16.
Dumitrescu AM, Liao XH, Weiss RE, Millen K, Refetoff S: Tissue-specific thyroid hormone deprivation and excess in monocarboxylate transporter (mct) 8-deficient mice. Endocrinology 2006;147:4036-4043.
17.
Wemeau JL, Pigeyre M, Proust-Lemoine E, D'Herbomez M, Gottrand F, Jansen J, Visser TJ, Ladsous M: Beneficial effects of propylthiouracil plus L-thyroxine treatment in a patient with a mutation in MCT8. J Clin Endocrinol Metab 2008;93:2084-2088.
18.
Verge CF, Konrad D, Cohen M, Di Cosmo C, Dumitrescu AM, Marcinkowski T, Hameed S, Hamilton J, Weiss RE, Refetoff S: Diiodothyropropionic acid (DITPA) in the treatment of MCT8 deficiency. J Clin Endocrinol Metab 2012;97:4515-4523.
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2015
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