Prenatal treatment of thyroid hormone cell membrane transport defect caused by MCT8 gene mutation

BACKGROUND Mutations of the thyroid hormone (TH) specific cell membrane transporter, monocarboxylate transporter 8 (MCT8), produce an X-chromosome linked syndrome of TH deficiency in brain and excess in peripheral tissues. The clinical consequences include brain hypothyroidism causing severe psychoneuromotor abnormalities (no speech, truncal hypotonia and spastic quadriplegia) and hypermetabolism (poor weight gain, tachycardia and increased metabolism, associated with high serum levels of the active TH, T3). Treatment in infancy and childhood with TH analogues that reduce serum T3, correct the hypermetabolism but have no effect on the psychoneuromotor deficits. Studies of brain from a 30 week old MCT8 deficient embryo indicated that brain abnormalities were already present during fetal life. METHODS A carrier woman with an affected male child (MCT8 A252fs268*), pregnant with a second affected male embryo, elected to carry the pregnancy to term. We treated the fetus with weekly 500 µg intra-amniotic instillation of levothyroxine (L-T4) from 18 weeks of gestation until birth at 35 weeks. T4, T3 and TSH were measured in the amniotic fluid and maternal serum. Treatment after birth was continued with L-T4 and propylthiouracil. Follow up included brain magnetic resonance imaging (MRI) and neurodevelopmental evaluation both compared to the untreated brother. RESULTS During intrauterine life T4 and T3 in the amniotic fluid were maintained above 3- to 2-fold the baseline and TSH was suppressed by 80%, while maternal serum levels remained unchanged. At birth the infant serum T4 was 14.5 µg/dL and TSH 8 mU/L respectively. MRI at 6 months of age showed near normal brain myelination compared to much reduced in the untreated brother. Neurodevelopmental assessment showed developmental quotients in receptive language, problem-solving, gross motor and fine motor function ranged from 12 to 25 at 31 month in the treated boy and 1 to 7 at 58 months in the untreated brother. CONCLUSIONS This is the first demonstration that prenatal treatment improved the neuromotor and neurocognitive function in MCT8 deficiency. Earlier treatment with TH analogues that concentrate in fetus when given to the mother may further rescue the phenotype.