Metabolic Brain Disease

, Volume 34, Issue 6, pp 1565–1575 | Cite as

Novel mutations in SLC16A2 associated with a less severe phenotype of MCT8 deficiency

  • Silvia Masnada
  • Stefan Groenweg
  • Veronica Saletti
  • Luisa Chiapparini
  • Barbara Castellotti
  • Ettore Salsano
  • W. Edward Visser
  • Davide TondutiEmail author
Original Article


Mutations in the thyroid hormone transporter MCT8 cause severe intellectual and motor disability and abnormal serum thyroid function tests, a syndrome known as MCT8 deficiency (or: Allan-Herndon-Dudley syndrome, AHDS). Although the majority of patients are unable to sit or walk independently and do not develop any speech, some are able to walk and talk in simple sentences. Here, we report on two cases with such a less severe clinical phenotype and consequent gross delay in diagnosis. Genetic analyses revealed two novel hemizygous mutations in the SLC16A2 gene resulting in a p.Thr239Pro and a p.Leu543Pro substitution in the MCT8 protein. In vitro studies in transiently transfected COS-1 and JEG-3 cells, and ex vivo studies in patient-derived fibroblasts revealed substantial residual uptake capacity of both mutant proteins (Leu543Pro > Thr239Pro), providing an explanation for the less severe clinical phenotype. Both mutations impair MCT8 protein stability and interfere with proper subcellular trafficking. In one of the patients calcifications were observed in the basal ganglia at the age of 29 years; an abnormal neuroradiological feature at this age that has been linked to untreated (congenital) hypothyroidism and neural cretinism. Our studies extend on previous work by identifying two novel pathogenic mutations in SLC16A2 gene resulting in a mild clinical phenotype.


MCT8 Leukoencephalopathy Cerebral calcifications MCT8 deficiency Thyroid hormone Thyroid hormone transporter 



We thank Ramona E.A. van Heerebeek and Selmar Leeuwenburgh for the technical assistance, the Optical Imaging Center (Erasmus Medical Center Rotterdam) for technical support regarding the confocal imaging studies, and the physicians of the involved patients and healthy controls for providing the fibroblasts.

Financial support

This work was supported by a grant from the Netherlands Organisation for Health Research and Development (project number 113303005) (to WEV), from the Sherman Foundation (to WEV).

Compliance with ethical standards

Conflict of interest

All authors declare no conflict of interest.

Disclosure statement

The authors have nothing to disclose.


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Pediatric Neurology UnitV. Buzzi Children’s HospitalMilanItaly
  2. 2.Department of Brain and Behavioural SciencesUniversity of PaviaPaviaItaly
  3. 3.Department of Internal Medicine, Academic Center for Thyroid DiseasesErasmus MC, University Medical CenterRotterdamThe Netherlands
  4. 4.Child Neurology DepartmentIRCCS Foundation C. Besta Neurological InstituteMilanItaly
  5. 5.Neuroradiology UnitIRCCS Foundation C. Besta Neurological InstituteMilanItaly
  6. 6.Unit of Genetics of Neurodegenerative and Metabolic DiseasesIRCCS Foundation C. Besta Neurological InstituteMilanItaly
  7. 7.Unit of Neurodegenerative and Neurometabolic Rare DiseasesIRCCS Foundation C. Besta Neurological InstituteMilanItaly

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