A nationwide survey of monocarboxylate transporter 8 deficiency in Japan: Its incidence, clinical course, MRI and laboratory findings



      Monocarboxylate transporter 8 (MCT8) deficiency is an X-linked recessive developmental disorder characterized by initially marked truncal hypotonia, later athetotic posturing, and severe intellectual disability caused by mutations in SLC16A2, which is responsible for the transport of triiodothyronine (T3) into neurons. We conducted a nationwide survey of patients with MCT8 deficiency to clarify their current status.


      Primary survey: In 2016–2017, we assessed the number of patients diagnosed with MCT8 deficiency from 1027 hospitals. Secondary survey: in 2017–2018, we sent case surveys to 31 hospitals (45 cases of genetic diagnosis), who responded in the primary survey. We asked for: 1) perinatal history, 2) developmental history, 3) head MRI findings, 4) neurophysiological findings, 5) thyroid function tests, and 5) genetic test findings.


      We estimated the prevalence of MCT8 deficiency to be 1 in 1,890,000 and the incidence of MCT8 deficiency per million births to be 2.12 (95 % CI: 0.99–3.25). All patients showed severe psychomotor retardation, and none were able to walk or speak. The significantly higher value of the free T3/free T4 (fT3/fT4) ratio found in our study can be a simple and useful diagnostic biomarker (Our value 11.60 ± 4.14 vs control 3.03 ± 0.38). Initial white matter signal abnormalities on head MRI showed recovery, but somatosensory evoked potentials (SEP) showed no improvement, suggesting that the patient remained dysfunctional.


      For early diagnosis, including in mild cases, it might be important to consider the clinical course, early head MRI, SEP, and fT3/fT4 ratio.


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        • Allan W.
        • Herndon C.N.
        • Dudley F.C.
        Some examples of the inheritance of mental deficiency: apparently sex-linked idiocy and microcephaly.
        Am J Ment Defic. 1994; 48: 325-334
        • Schwartz C.E.
        • May M.M.
        • Carpenter N.J.
        • Rogers R.C.
        • Martin J.
        • Bialer M.G.
        • et al.
        Allan-Herndon-Dudley syndrome and the monocarboxylate transporter 8 (MCT8) gene.
        Am J Hum Genet. 2005; 77: 41-53
      1. Sarret C, Oliver Petit I, Tonduti D. Allan-Herndon-Dudley syndrome. 2010 Mar 9 [updated 2020 Jan 16]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Gripp KW, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2022.

        • Groeneweg S.
        • Peeters R.P.
        • Moran C.
        • Stoupa A.
        • Auriol F.
        • Tonduti D.
        • et al.
        Effectiveness and safety of the tri-iodothyronine analogue Triac in children and adults with MCT8 deficiency: an international, single-arm, open-label, phase 2 trial.
        Lancet Diabetes Endocrinol. 2019; 7: 695-706
        • Schwartz C.E.
        • Stevenson R.E.
        The MCT8 thyroid hormone transporter and Allan-Herndon-Dudley syndrome.
        Best Pract Res Clin Endocrinol Metab. 2007; 21: 307-321
        • Groeneweg S.
        • van Geest F.S.
        • Abacı A.
        • Alcantud A.
        • Ambegaonkar G.P.
        • Armour C.M.
        • et al.
        Disease characteristics of MCT8 deficiency: an international, retrospective, multicentre cohort study.
        Lancet Diabetes Endocrinol. 2020; 8: 594-605
        • Oto Y.
        • Muroya K.
        • Hanakawa J.
        • Asakura Y.
        • Adachi M.
        The ratio of serum free triiodothyronine to free thyroxine in children: a retrospective database survey of healthy short individuals and patients with severe thyroid hypoplasia or central hypothyroidism.
        Thyroid Res. 2015; 8: 10
        • Taylor M.J.
        • Fagan E.R.
        SEPs to median nerve stimulation: normative data for paediatrics.
        Electroencephalogr Clin Neurophysiol. 1988; 71: 323-330
        • Visser W.E.
        • Vrijmoeth P.
        • Visser F.E.
        • Arts W.F.M.
        • van Toor H.
        • Visser T.J.
        Identification, functional analysis, prevalence and treatment of monocarboxylate transporter 8 (MCT8) mutations in a cohort of adult patients with mental retardation.
        Clin Endocrinol (Oxf). 2013; 78: 310-315
        • Remerand G.
        • Boespflug-Tanguy O.
        • Tonduti D.
        • Touraine R.
        • Rodriguez D.
        • Curie A.
        • et al.
        Expanding the phenotypic spectrum of Allan-Herndon-Dudley syndrome in patients with SLC16A2 mutations.
        Dev Med Child Neurol. 2019; 61: 1439-1447
        • Vancamp P.
        • Demeneix B.A.
        • Remaud S.
        Monocarboxylate Transporter 8 deficiency: delayed or permanent hypomyelination?.
        Front Endocrinol (Lausanne). 2020; 11: 283
        • López-Espíndola D.
        • Morales-Bastos C.
        • Grijota-Martínez C.
        • Liao X.-H.
        • Lev D.
        • Sugo E.
        • et al.
        Mutations of the thyroid hormone transporter MCT8 cause prenatal brain damage and persistent hypomyelination.
        J Clin Endocrinol Metab. 2014; 99: E2799-E2804
        • Heuer H.
        • Maier M.K.
        • Iden S.
        • Mittag J.
        • Friesema E.C.H.
        • Visser T.J.
        • et al.
        The monocarboxylate transporter 8 linked to human psychomotor retardation is highly expressed in thyroid hormone-sensitive neuron populations.
        Endocrinology. 2005; 146: 1701-1706