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TRIAC treatment of an infant with Allan-Herndon-Dudley Syndrome (AHDS): Effects on iodothyronines in serum and cerebrospinal fluid

AutorIglesias, Ainhoa; Palomares, María; Morte, Beatriz ; Obregón, María Jesús; Bernal, Juan
Fecha de publicación2014
CitaciónETA 2014
ResumenAllan-Herndon-Dudley Syndrome (AHDS) is a devastating disease caused by defects in the thyroid hormone (TH) transporter MCT8. Systemic hyperthyroidism is heralded by elevated serum T3 (with mildly increased TSH and decreased T4). However, the brain is hypothyroid, causing incapacitating psychomotor retardation. Therapeutic attempts with PTU+Levothyroxine or the T3-analogue DITPA could normalize TH derangements without neurological improvement. Recently, administration of TETRAC to Mct8 KO mice corrected TH abnormalities in this model for AHDS. [Objective]: To determine the TH metabolic and developmental effects of TRIAC (a rapidly-generated metabolite of TETRAC) in a child with earlydiagnosed AHDS. [Patient and Methods]: 8-month-old male with severe axial hypotonia, psychomotor retardation and apparent hypothyroidism (TSH 7.7 mU/L, FT4 0.48 ng/dL) but elevated FT3 (8.86 pg/mL). Thyroid-targeted CGH array (Thyroarray©). Compassionate treatment with increasing doses of TRIAC (10-40 μg/kg/day) for 1 year. Follow-up: TH profiles, brain MRI and psychometry (Brunet-Lezine) every 3 months. Radioimmunoassay of T4, T3 and TRIAC in cerebrospinal fluid (CSF) of patient and 14 age-matched controls. [Results]: Novel de novo MCT8 deletion spanning 25.04 Kb from mid-exon 3. TRIAC normalized FT3 and TSH (4.1 pg/mL and 1.2 mU/L) but reduced FT4 (0.3 ng/dL). Brain myelination progressed 5 months after 9-months treatment. After initial improvement of motor (18% to 40%) and social-language (at 70-72%) at 3 months, developmental achievements slowed-down at 1 year (30% and 55%, respectively). In CSF, TRIAC was 5 ng/dL (N: 1.4-4.7) before trial's start, increasing to 8.4 ng/dL at highest TRIAC dose. T4 was low (50.2 ng/dL; N: 65-166), further decreasing under TRIAC (19.2 ng/dL). T3 was low, before and after treatment (0.7 and 1.06 ng/dL; N: 1.9-2.85). [Conclusions]: TRIAC normalizes serum FT3 and TSH, but decreases FT4, requiring L-T4 substitution. After initial improvement of milestone acquisition, developmental deceleration occurred. Iodothyronines in CSF are low irrespective of treatment, suggesting blood-CSF barrier transport of T3-T4 is restricted in AHDS.
DescripciónResumen del trabajo presentado al 38th Annual Meeting of the European Thyroid Association celebrado en Santiago de Compostela (España) del 6 al 10 de septiembre de 2014.-- et al.
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