Awareness of MCT8 deficiency causing abnormal thyroid hormone transport may help early diagnosis

medwireNews: An extensive multinational study of patients with disordered thyroid hormone transport due to MCT8 deficiency has identified key characteristics that could help early diagnosis and the treatment of underlying risk factors associated with a poor outcome in affected patients.

“Disordered thyroid hormone transport, due to mutations in the SLC16A2 gene encoding monocarboxylate transporter 8 (MCT8) is characterised by intellectual and motor disability resulting from cerebral hypothyroidism and chronic peripheral thyrotoxicosis”, explain W Edward Visser, from Erasmus Medical Centre Rotterdam in the Netherlands, and co-workers.

The team collated medical records for 151 patients in 22 countries who had 73 different SLCA16A2 mutations. The patients developed their first symptoms at a median age of 4.0 months, most commonly gross developmental delay (79%), hypotonia (49%), and poor weight gain (10%) or feeding problems (7%), and were diagnosed with MCT8 deficiency at a median age of 24.0 months.

The patients showed moderate-to-severe intellectual disability, alongside severe delays in motor and language development, with no indication of improvement in motor or cognitive abilities over time, the researchers say.

All 13 of the patients who underwent magnetic resonance imaging of the brain at a median age of 8 months had global delay in myelination that improved at follow-up but did not reach normal-for-age levels.

Serum thyroid tests performed at a median age of 5.3 years showed that 89% of tested patients had thyroid stimulating hormone (TSH) concentrations within the normal range but that free and total thyroxine (T4) levels were below the age-specific lower limit in 89% and 90% of patients, respectively. In addition, 95% of patients had a serum triiodothyronine (T3) concentration above the age-specific limit, resulting in a “pronounced increase” in the T3 to T4 ratio.

“The low concentrations of thyroxine measured in the neonatal screening indicates that current neonatal screening strategy, , has the potential to detect MCT8 deficiency”, using T4 as the determined hormone, say Visser et al in The Lancet Diabetes & Endocrinology.

“These observations hinting at the possibility of early diagnosis are particularly relevant in the context of Triac therapy recently reported, which has the potential to ameliorate the devastating course of the disorder if left untreated”, they write.

In an accompanying comment, Ari Wassner, from Boston Children’s Hospital in Massachusetts, USA, agrees that, while “premature” to consider shifting newborn screening to thyroxine instead of the currently used TSH measurements, he believes that “there is mounting evidence that congenital hypothyroidism of central origin is both more common (1 in 16 000–20 000) and more severe than previously recognised.”

“If these discoveries encourage a broader shift towards [thyroxine]-based newborn screening, and if Triac fulfils its promise to rescue the postnatal brain from the ravages of thyroid hormone deficiency, there is reason to hope that the devastating course of MCT8 deficiency might one day be substantially changed”, he says.

Overall, 21% of the patients died at a median age of 10.5 years and median overall survival was 35.0 years, with 10-year, 18-year and 60-year survival rates estimated to be 85%, 70% and 35%. Several characteristics significantly predicted mortality – lack of head control by age 1.5 years (hazard ratio [HR]=3.46) and being underweight at age 1–3 years compared with normal weight (HR=4.71).

Almost a fifth (19%) of deaths were attributed to respiratory infection and 9% to aspiration pneumonia. Noting that 71% of patients had impaired swallowing but just 36% were tube fed, Wassner hypothesises that “increased use of tube feeding might prevent fatal aspiration pneumonia in this population.”

In addition, the commentator notes that sudden death occurred in 19% of patients. Citing the “remarkably high” rates of tachycardia, hypertension, aortic root dilation, and arrhythmias in the study cohort, he says that “this study makes it clear that cardiac evaluation is crucial – and potentially life-saving – in patients with MCT8 deficiency.”

By Lynda Williams

medwireNews is an independent medical news service provided by Springer Healthcare. © 2020 Springer Healthcare part of the Springer Nature Group

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