Type of Mutations: RTT is mainly caused by commonly sporadic (de novo) and rarely familial mutations of MECP2 gene. These mutations, occurring mainly at CpG hotspot sites due to high germline methylation, originate spontaneously in paternal germ cells. This gene works as a translational regulator which is critical for normal synaptic functions and neurodevelopment. Over 95% of classic RTT cases involve MECP2 mutations, with additional complexity introduced by X-chromosome inactivation patterns in females which connects RTT closely to epigenetic regulation.
MECP2 has two isoforms as MECP2E1 (previously MECP2B or MECP2α) and MECP2E2 (previously MECP2A or MECP2β). MECP2E1 is the predominant isoform in Central Nervous System (CNS). Studies confirmed that most common variants include missense, nonsense, frameshift and in-frame insertions and deletions. Complex chromosomal rearrangements also may occur in MECP2.
Eight important variants are responsible for 60 % of all cases which include:
p.Arg106Trp (R106W)
p.Arg133Cys (R133C)
p.Thr158Met (T158M)
p.Arg168* (R168X)
p.Arg255* (R255X)
p.Arg270* (R270X)
p.Arg294*(R294X)
p.Arg306Cys (R306X)
Variants p.Arg106Trp, p.Arg168*, p.Arg255* and p.Arg270* are associated with the most severe clinical findings, whereas p.Arg133Cys, p.Arg294* and p.Arg306Cys variants tend to cause mild RTT; and p.Thr158Met is associated with moderate severity.
The binding of MeCP2 protein to methylated DNA effect the expression of thousands of other genes. Neuropathological, neurochemical and neuroimaging studies indicate that RTT is a widespread, multiregion and multineurotransmitter system disorder characterized by volumetric reduction, from cellular to brain regional levels, and atypical astrocytes, in the absence of features of neurodegeneration. Multiple studies have shown that selective deletion of MECP2 in different brain areas and neuronal subtypes results in specific phenotypes associated with dysfunction of the affected region or the local circuit.
Transcription failure: Neural activity-dependent MeCP2 phosphorylation seems to influence its transcriptional regulatory role and dendritic development. Neuropathological and magnetic resonance spectroscopy studies in individuals with RTT show evidence of increased number of astrocytes and increased expression of astrocytic markers (for example, GFAP and myo-inositol).
Neuronal and synaptic alterations: These changes also result in structural and functional consequencies at the neuronal and synaptic levels. Reduction in brain volume especially in dorsal parietal cortex is considered to be the consequence of neuraonal and synaptic aterations.
Neurotransmitter affect: MeCP2 has been shown to affect all neurotransmitter systems and brain areas investigated in animal models and in human brain and CSF samples. Early focus on aminergic systems was based on behavioural alterations observed in individuals with RTT, while individual monoamine systems have been linked to specific disease domains including breathing (noradrenaline) and motor function (dopamine).
Mitochondrial dysfunction: In RTT, cells contain lower levels of Parkin and impaired translocation of PINK1 to the mitochondria, both of which are essential for the initiation of mitophagy. RTT cells fail to degrade mitochondrial proteins, such as MFN2 and ATP5A, following mitochondrial damage.
Apoptosis: Mecp2-e2 isoform promotes neuronal death, while FoxG1 normally promotes neuronal survival. Mecp2 knockout neurons are more susceptible to hypoxia-induced cell death.
Diagnostic testing: Diagnosis of RTT is based on the 2010 consensus criteria, a revision of previous guidelines, which require the presence of developmental regression following an apparently normal early postnatal period. About 85 % of individuals fulfil criteria of classical RTT. challenges in diagnosing and surveying males with MECP2 variants, and increasing access to MECP2 testing and genomic sequencing are crucial to identify these cases.
MECP2