Atypical processing of tones and phonemes in Rett Syndrome as biomarkers of disease progression

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Abstract

Due to severe motor impairments and the lack of expressive language abilities seen in most patients with Rett Syndrome (RTT), it has proven extremely difficult to obtain accurate measures of auditory processing capabilities in this population. Here, we examined early auditory cortical processing of pure tones and more complex phonemes in females with Rett Syndrome (RTT), by recording high-density auditory evoked potentials (AEP), which allow for objective evaluation of the timing and severity of processing deficits along the auditory processing hierarchy. We compared AEPs of 12 females with RTT to those of 21 typically developing (TD) peers aged 4–21 years, interrogating the first four major components of the AEP (P1: 60–90 ms; N1: 100–130 ms; P2: 135–165 ms; and N2: 245–275 ms). Atypicalities were evident in RTT at the initial stage of processing. Whereas the P1 showed increased amplitude to phonemic inputs relative to tones in TD participants, this modulation by stimulus complexity was absent in RTT. Interestingly, the subsequent N1 did not differ between groups, whereas the following P2 was hugely diminished in RTT, regardless of stimulus complexity. The N2 was similarly smaller in RTT and did not differ as a function of stimulus type. The P2 effect was remarkably robust in differentiating between groups with near perfect separation between the two groups despite the wide age range of our samples. Given this robustness, along with the observation that P2 amplitude was significantly associated with RTT symptom severity, the P2 has the potential to serve as a monitoring, treatment response, or even surrogate endpoint biomarker. Compellingly, the reduction of P2 in patients with RTT mimics findings in animal models of RTT, providing a translational bridge between pre-clinical and human research.

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Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2.

Ruthie Amir, Ignatia B Van den Veyver, Mimi Wan … (1999)

Rett syndrome (RTT, MIM 312750) is a progressive neurodevelopmental disorder and one of the most common causes of mental retardation in females, with an incidence of 1 in 10,000-15,000 (ref. 2). Patients with classic RTT appear to develop normally until 6-18 months of age, then gradually lose speech and purposeful hand use, and develop microcephaly, seizures, autism, ataxia, intermittent hyperventilation and stereotypic hand movements. After initial regression, the condition stabilizes and patients usually survive into adulthood. As RTT occurs almost exclusively in females, it has been proposed that RTT is caused by an X-linked dominant mutation with lethality in hemizygous males. Previous exclusion mapping studies using RTT families mapped the locus to Xq28 (refs 6,9,10,11). Using a systematic gene screening approach, we have identified mutations in the gene (MECP2 ) encoding X-linked methyl-CpG-binding protein 2 (MeCP2) as the cause of some cases of RTT. MeCP2 selectively binds CpG dinucleotides in the mammalian genome and mediates transcriptional repression through interaction with histone deacetylase and the corepressor SIN3A (refs 12,13). In 5 of 21 sporadic patients, we found 3 de novo missense mutations in the region encoding the highly conserved methyl-binding domain (MBD) as well as a de novo frameshift and a de novo nonsense mutation, both of which disrupt the transcription repression domain (TRD). In two affected half-sisters of a RTT family, we found segregation of an additional missense mutation not detected in their obligate carrier mother. This suggests that the mother is a germline mosaic for this mutation. Our study reports the first disease-causing mutations in RTT and points to abnormal epigenetic regulation as the mechanism underlying the pathogenesis of RTT.