5q14.3 deletions spanning and flanking MEF2C as well as intragenic MEF2C mutations have recently been described as a cause of severe intellectual disability, epilepsy, and muscular hypotonia, with variable brain and other anomalies.
The purpose of this work was to clarify criteria for the selection of patients with severe intellectual disability to screen for deficiency in the MEF2C gene.
Mutations in MEF2C from the 5q14.3q15 microdeletion syndrome region are a frequent cause of severe mental retardation and diminish MECP2 and CDKL5 expression.
Severe intellectual disability with inability to speak and epilepsy are universal features in patients with MEF2C mutations, although mild cognitive and speech disorders have been reported to occur in patients with duplications.
Severe mental retardation with breathing abnormalities (Pitt-Hopkins syndrome) is caused by haploinsufficiency of the neuronal bHLH transcription factor TCF4.
Haploinsufficiency of the gene encoding for transcription factor 4 (TCF4) was recently identified as the underlying cause of Pitt-Hopkins syndrome (PTHS), an underdiagnosed mental-retardation syndrome characterised by a distinct facial gestalt, breathing anomalies and severe mental retardation.
Taken together, these results strongly suggest that haploinsufficiency of MEF2C is responsible for severe mental retardation with stereotypic movements, seizures and/or cerebral malformations.
Mutations in the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) prevent appropriate entry of thyroid hormones into brain cells during development and cause severe mental retardation in affected patients.
Recently, the monocarboxylate transporter 8 (MCT8) was identified as a thyroid hormone transporter, and MCT8 mutations have been associated with Allan-Herndon-Dudley syndrome, an X linked condition characterized by severe mental retardation, dysarthria, athetoid movements, muscle hypoplasia, and spastic paraplegia.
Our results show the difficulty of distinguishing AHDS from patients with X-linked intellectual disability solely on the basis of clinical features and biochemical tests, and we advise screening for MCT8 mutations in either young or older patients with severe intellectual disability, axial hypotonia/dystonia, poor head control, spastic paraplegia, and athetoid movements even when they have normal thyroid hormone profiles.
Recently mutations in the SLC16A2 gene coding for the monocarboxylate thyroid hormone transporter 8, MCT8, have been associated with Allan-Herndon-Dudley syndrome (AHDS), an X-linked condition characterized by severe mental retardation, dysarthria, athetoid movements, muscle hypoplasia and spastic paraplegia.
We report a novel 1 bp deletion (c.1834delC) in the MCT8 gene in a large Brazilian family with Allan-Herndon-Dudley syndrome (AHDS), an X linked condition characterised by severe mental retardation and neurological dysfunction.
FOXG1-related disorders, caused by deletions, intragenic mutations or duplications, are usually associated with severe intellectual disability, autistic features, and, in 87% of subjects, epileptiform manifestations.