Mutations in the thyroid monocarboxylate transporter 8 gene (MCT8/SLC16A2) have 
been reported to result in X-linked mental retardation (XLMR) in patients with 
clinical features of the Allan-Herndon-Dudley syndrome (AHDS). We performed MCT8 
mutation analysis including 13 XLMR families with LOD scores >2.0, 401 male MR 
sibships and 47 sporadic male patients with AHDS-like clinical features. One 
nonsense mutation (c.629insA) and two missense changes (c.1A>T and c.1673G>A) 
were identified. Consistent with previous reports on MCT8 missense changes, the 
patient with c.1673G>A showed elevated serum T3 level. The c.1A>T change in 
another patient affects a putative translation start codon, but the same change 
was present in his healthy brother. In addition normal serum T3 levels were 
present, suggesting that the c.1A>T (NM_006517) variation is not responsible for 
the MR phenotype but indicates that MCT8 translation likely starts with a 
methionine at position p.75. Moreover, we characterized a de novo translocation 
t(X;9)(q13.2;p24) in a female patient with full blown AHDS clinical features 
including elevated serum T3 levels. The MCT8 gene was disrupted at the 
X-breakpoint. A complete loss of MCT8 expression was observed in a fibroblast 
cell-line derived from this patient because of unfavorable nonrandom 
X-inactivation. Taken together, these data indicate that MCT8 mutations are not 
common in non-AHDS MR patients yet they support that elevated serum T3 levels 
can be indicative for AHDS and that AHDS clinical features can be present in 
female MCT8 mutation carriers whenever there is unfavorable nonrandom 
X-inactivation.