X-Linked MCT8 Gene Mutations: Characterization of the Pediatric Neurologic Phenotype

Greenwood Genetic Center, Greenwood, SC, USA.
Journal of Child Neurology (Impact Factor: 1.72). 11/2005; 20(10):852-7. DOI: 10.1177/08830738050200101601
Source: PubMed


We report a family with X-linked mental retardation that has a novel mutation in the monocarboxylate transporter 8 (MCT8) gene associated with a characteristic neurodevelopmental phenotype with early childhood hypotonia that progresses to spasticity and global developmental delays. Affected patients experience moderate to severe psychomotor delays and congenital hypotonia, develop a myopathic facies, have diminished muscle bulk and generalized muscle weakness, develop progressive spasticity and movement disorders, and have limited speech but alert, affable personalities. Acquired microcephaly and abnormal myelination on brain magnetic resonance imaging can be present. Normal monocarboxylate transporter 8 gene functioning appears to be necessary for normal thyroid-associated metabolism in neurons. Abnormal thyroid function tests appear to be a consistent finding in the absence of typical signs of thyroid dysfunction. Although the phenotype appears to be consistent, and although the neurotoxic effects of abnormal central and peripheral neuromuscular system thyroid metabolism might be partly or wholly responsible for the neurologic phenotype reported, the exact mechanism remains unclear.

1 Follower
5 Reads
  • Source
    • "In addition to the clinical and biological features of patients with SLC16A2 mutations, some authors have reported a nonspecific myelination delay [Holden et al., 2005; Namba et al., 2008] and spectroscopic abnormalities [Sijens et al., 2008]. More recently, the identification of SLC16A2 mutations in a series of patients initially considered as presenting with a severe Pelizaeus–Merzbacher-like disease (PMD) in their first years of life has confirmed this association with delayed myelination [Gika et al., 2010; Vaurs - Barrì ere et al., 2009] . "
    [Show abstract] [Hide abstract]
    ABSTRACT: SLC16A2, the gene for the 2(nd) member of the solute carrier family 16 (monocarboxylic acid transporter), located on chromosome Xq13.2, encodes a very efficient thyroid hormone (TH) transporter: monocarboxylate transporter 8, MCT8. Its loss of function is responsible in males for a continuum of psychomotor retardation ranging from severe (no motor acquisition, no speech) to mild (ability to walk with help and a few words of speech). Triiodothyronine uptake measurement in transfected cells and, more recently, patient fibroblasts, has been described to study the functional consequences of MCT8 mutations. Here we describe 3 novel MCT8 mutations, including one missense variation not clearly predicted to be damaging but found in a severely affected patient. Functional studies in fibroblasts and JEG3 cells demonstrate the usefulness of both cellular models in validating the deleterious effects of a new MCT8 mutation if there is still a doubt as to its pathogenicity. Moreover, the screening of fibroblasts from a large number of patient fibroblasts and of transfected mutations has allowed us to demonstrate that JEG3 transfected cells are more relevant than fibroblasts in revealing a genotype-phenotype correlation.
    Human Mutation 07/2013; 34(7). DOI:10.1002/humu.22331 · 5.14 Impact Factor
  • Source
    • "In the brain, thyroid hormone is required for the timely migration of neurons, formation of synaptic contacts, and myelination (Zoeller et al. 2002). Since MCT8 is expressed, among other tissues, in neurons and pituitary cells (Heuer et al. 2005), it has been expected that mutations in MCT8 may deprive developing neurons of adequate T 3 signalling leading to mental impairment, albeit, the phenotypes of MCT8- deficient patients are not compatible with untreated congenital hypothyroidism (Dumitrescu et al. 2004, Friesema et al. 2004, Holden et al. 2005, Kakinuma et al. 2005, Schwartz et al. 2005, Maranduba et al. 2006, Herzovich et al. 2007, Jansen et al. 2007). In addition, the apparent lack of feedback inhibition of TSH expression in the pituitary suggests that pituitary thyrotroph cells are not able to correctly sense circulating T 3 levels. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Mutations in the gene encoding the thyroid hormone transporter, monocarboxylate transporter 8 (MCT8), underlie severe mental retardation. We wanted to understand the functional consequences of a series of missense mutations in MCT8 in order to identify therapeutic options for affected patients. We established cell lines stably expressing 12 MCT8 variants in JEG1 and MDCK1 cells. The cell lines were characterized according to MCT8 mRNA and protein expression, tri-iodothyronine (T(3)) transport activity, substrate K(M) characteristics, surface expression, and responsiveness to T(3) preincubation and chemical chaperones. Functional activities of ins235V and L568P MCT8 mutants depend on the cell type in which they are expressed. These mutants and R271H exhibited considerable transport activity when present at the cell surface as verified by surface biotinylation and kinetic analysis. Most mutants, however, were inactive in T(3) transport even when present at the cell surface (e.g. S194F, A224V, DeltaF230, L512P). Preincubation of G558D with T(3) increased T(3) uptake in MDCK1 cells to a small, but significant, extent. Chemical chaperones were ineffective. The finding that the cell type determines surface expression and T(3) transport activities of missense mutants in MCT8 may be important to understand phenotypic variability among carriers of different mutations. In particular, the clinical observation that the severity of derangements of thyroid hormone levels does not correlate with mental impairments of the patients may be based on different residual activity of mutant MCT8 in different cell types.
    Journal of Molecular Endocrinology 08/2009; 43(6):263-71. DOI:10.1677/JME-09-0043 · 3.08 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Iterative feedback tuning (IFT) is a data-based method for the tuning of restricted complexity controllers. At each iteration, an update for the parameters of the controller is estimated from data obtained partly from the normal operation of the closed loop system and partly from a special experiment. The choice of a prefilter for the input data to the special experiment is a degree of freedom of the method. In the present contribution, the prefilter is designed in order to enhance the accuracy of the IFT update.
    Decision and Control, 2003. Proceedings. 42nd IEEE Conference on; 01/2004
Show more