Prenatal Treatment of Thyroid Hormone Cell Membrane Transport Defect Caused by <i>MCT8</i> Gene Mutation

Refetoff, Samuel; Παππά, Θεοδώρα; Williams, Meredith K.; Matheus, Maria Gisele; Liao, Xiao Hui; Hansen, Karen; Nicol, Lindsey; Pierce, Melinda; Blasco, Peter A.; Jensen, Mandie Wiebers; Bernal, Juan; Weiss, Roy E.; Dumitrescu, Alexandra M.; LaFranchi, Stephen

doi:10.1089/thy.2020.0306

Cited by 19 publications

(28 citation statements)

References 29 publications

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“…In fact 6 and 4 of 8 DBS samples from newborns with MCT8 deficiency had total T4 values that were 1 and 2 SDs, respectively, below the mean value ( 10 ). In another report of 8 MCT8-deficient newborn, the mean total T4 was 5.1 ± 1.6 μg/dL with a range of 3.1–8.4, compared with a reference range of 6–15 μg/dL ( 11 ).…”

Section: Discussionmentioning

confidence: 95%

“…With reduction in cost of LC-MS/MS measurement and the increase in survival and cost for the care of individuals with MCT8 deficiency, the application of LC-MS/MS in neonatal screening is possible. Although current treatments of MCT8 deficiency are at best palliative, more effective early treatment using TH analogues ( 2 ) and gene-directed treatments are under development ( 11 , 20 ).…”

Section: Discussionmentioning

confidence: 99%

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Measurement of Reverse Triiodothyronine Level and the Triiodothyronine to Reverse Triiodothyronine Ratio in Dried Blood Spot Samples at Birth May Facilitate Early Detection of Monocarboxylate Transporter 8 Deficiency

Iwayama

Kakita

Iwasa

et al. 2021

Thyroid

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Background: Monocarboxylate transporter 8 (MCT8) deficiency is an X-chromosome-linked neurodevelopmental disorder resulting from impaired thyroid hormone transport across the cell membrane. The diagnosis of MCT8 deficiency is typically delayed owing to the late appearance of signs and symptoms as well as the inability of standard biomarkers of neonatal screening to provide early detection. In this study, we report, for the first time, the ability to detect MCT8 deficiency at birth using dried blood spot (DBS) samples. Methods: We retrospectively measured triiodothyronine (T3), thyroxine (T4), and reverse T3 (rT3) levels in DBS samples obtained at 4–5 days of life from 6 infants with genetically confirmed MCT8 deficiency and from 110 controls. The latter consisted of 58 healthy term neonates obtained at the same time, 16 were stored for more than 1 year before measurement to match samples from the MCT8-deficient infants. Ten DBS samples were collected at day 1 of life and 42 samples were from prematurely born neonates. Measurements were carried out in extract from eight millimeters diameter DBS using liquid chromatography-tandem mass spectrometry. Results: Contrary to characteristic iodothyronine abnormalities of MCT8 deficiency during later life, T3 and T4 values were not discriminatory from those of other study groups. In contrast, rT3 was significantly lower. The T3/rT3 ratio was higher in the DBS samples from the MCT8-deficient infants compared with all other groups with no overlap ( p < 0.0001). Conclusions: rT3 and T3/rT3 ratio in DBS samples obtained from neonates can serve as biomarkers to detect MCT8 deficiency at birth.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Measurement of Reverse Triiodothyronine Level and the Triiodothyronine to Reverse Triiodothyronine Ratio in Dried Blood Spot Samples at Birth May Facilitate Early Detection of Monocarboxylate Transporter 8 Deficiency

Iwayama

Kakita

Iwasa

et al. 2021

Thyroid

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“…Following the experiences with T4 monotherapy, no alterations in the neurocognitive phenotype were observed upon treatment. Interestingly, neurocognitive improvement was observed upon intra-uterine instillation of T4 in one mother pregnant of a foetus with MCT8 deficiency, followed by T4 + PTU combination therapy after birth ( 87 ). It remains unclear why prenatal treatment had a beneficial effect on neurocognition, whereas this is not the case for postnatal treatment ( 9 , 78 ).…”

Section: Development Of (Potential) Therapiesmentioning

confidence: 99%

Monocarboxylate Transporter 8 Deficiency: From Pathophysiological Understanding to Therapy Development

et al. 2021

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Genetic defects in the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) result in MCT8 deficiency. This disorder is characterized by a combination of severe intellectual and motor disability, caused by decreased cerebral thyroid hormone signalling, and a chronic thyrotoxic state in peripheral tissues, caused by exposure to elevated serum T3 concentrations. In particular, MCT8 plays a crucial role in the transport of thyroid hormone across the blood-brain-barrier. The life expectancy of patients with MCT8 deficiency is strongly impaired. Absence of head control and being underweight at a young age, which are considered proxies of the severity of the neurocognitive and peripheral phenotype, respectively, are associated with higher mortality rate. The thyroid hormone analogue triiodothyroacetic acid is able to effectively and safely ameliorate the peripheral thyrotoxicosis; its effect on the neurocognitive phenotype is currently under investigation. Other possible therapies are at a pre-clinical stage. This review provides an overview of the current understanding of the physiological role of MCT8 and the pathophysiology, key clinical characteristics and developing treatment options for MCT8 deficiency.

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“…Kaplan-Meier estimates of MCT8-specific survival in patients who attained head control (red line) by the age of 1.5 years versus those who did not (blue line) (B) or were too old at treatment initiation to expect any improvements in neurodevelopment [2]. Refetoff et al [20] recently reported about treatment of a foetus with MCT8 deficiency with T4 installations during intrauterine life and with PTU and T4 combination therapy starting directly after birth. A remarkable improvement in neurodevelopment was observed at 2.5 years of age compared to his older, untreated brother harbouring the same mutation.…”

Section: Conventional Therapiesmentioning

confidence: 99%

Monocarboxylate transporter 8 deficiency: update on clinical characteristics and treatment

2021

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Defective thyroid hormone transport due to deficiency in thyroid hormone transporter monocarboxylate transporter 8 (MCT8) results in severe neurodevelopmental delay due to cerebral hypothyroidism and in clinical negative sequelae following a chronic thyrotoxic state in peripheral tissues. The life expectancy of patients with MCT8 deficiency is severely impaired. Increased mortality is associated with lack of head control and being underweight at young age. Treatment options are available to alleviate the thyrotoxic state; particularly, treatment with the thyroid hormone analogue triiodothyroacetic acid seems a promising therapy. This review provides an overview of key clinical features and treatment options available and under development for this rare disorder.

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Prenatal Treatment of Thyroid Hormone Cell Membrane Transport Defect Caused by MCT8 Gene Mutation

Cited by 19 publications

References 29 publications

Measurement of Reverse Triiodothyronine Level and the Triiodothyronine to Reverse Triiodothyronine Ratio in Dried Blood Spot Samples at Birth May Facilitate Early Detection of Monocarboxylate Transporter 8 Deficiency

Measurement of Reverse Triiodothyronine Level and the Triiodothyronine to Reverse Triiodothyronine Ratio in Dried Blood Spot Samples at Birth May Facilitate Early Detection of Monocarboxylate Transporter 8 Deficiency

Monocarboxylate Transporter 8 Deficiency: From Pathophysiological Understanding to Therapy Development

Monocarboxylate transporter 8 deficiency: update on clinical characteristics and treatment

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