Multimodal Neuroimaging in Rett Syndrome With MECP2 Mutation

Abstract

Rett syndrome (RTT) is a rare neurodevelopmental disorder characterized by severe cognitive, social, and physical impairments resulting from de novo mutations in the X-chromosomal methyl-CpG binding protein gene 2 (MECP2). While there is still no cure for RTT, exploring up-to date neurofunctional diagnostic markers, discovering new potential therapeutic targets, and searching for novel drug efficacy evaluation indicators are fundamental. Multiple neuroimaging studies on brain structure and function have been carried out in RTT-linked gene mutation carriers to unravel disease-specific imaging features and explore genotype-phenotype associations. Here, we reviewed the neuroimaging literature on this disorder. MRI morphologic studies have shown global atrophy of gray matter (GM) and white matter (WM) and regional variations in brain maturation. Diffusion tensor imaging (DTI) studies have demonstrated reduced fractional anisotropy (FA) in left peripheral WM areas, left major WM tracts, and cingulum bilaterally, and WM microstructural/network topology changes have been further found to be correlated with behavioral abnormalities in RTT. Cerebral blood perfusion imaging studies using single-photon emission CT (SPECT) or PET have evidenced a decreased global cerebral blood flow (CBF), particularly in prefrontal and temporoparietal areas, while magnetic resonance spectroscopy (MRS) and PET studies have contributed to unraveling metabolic alterations in patients with RTT. The results obtained from the available reports confirm that multimodal neuroimaging can provide new insights into a complex interplay between genes, neurotransmitter pathway abnormalities, disease-related behaviors, and clinical severity. However, common limitations related to the available studies include small sample sizes and hypothesis-based and region-specific approaches. We, therefore, conclude that this field is still in its early development phase and that multimodal/multisequence studies with improved post-processing technologies as well as combined PET–MRI approaches are urgently needed to further explore RTT brain alterations.

Evidence Synthesis of Gene Therapy and Gene Editing from Different Disorders—Implications for Individuals with Rett Syndrome: A Systematic Review

“…In a study of 28 girls with RTT (mean age (years) ± SD: 3.5 ± 1.25 years), MRI revealed structural brain abnormalities such as decreased grey matter in the insula, frontal cortex and limbic regions [97]. Diffusion MRI of Rett brains may also allow for finer details of brain microstructure to be revealed at various stages of development [98]. However, the modifications in brain architecture seen during MRI probably represent an epoch in RTT where changes are irreversible and would not be of benefit for pre-symptomatic screening.…”

Brain structural alterations in young girls with Rett syndrome: A voxel-based morphometry and tract-based spatial statistics study

“…Unlike idiopathic ASD, which has not been identified with a specific gene or set of genes, RTT is more of a monogenic disorder caused by MECP2 gene variants (Neul et al, 2008 , 2010 ). At the cellular level, the MECP2 gene has been tested to express widely throughout the mature neurons of the brain and plays a crucial role in synaptic plasticity, neuronal development, and differentiation (Chahrour et al, 2008 ; Lyst and Bird, 2015 ; Kong et al, 2022 ). Autopsy studies in patients with RTT revealed a reduction in brain weight and an overall decreased brain size (Armstrong et al, 1995 ; Bauman et al, 1995 ; Armstrong, 2005 ).…”

A Brain Morphometry Study with Across-Site Harmonization Using a ComBat-Generalized Additive Model in Children and Adolescents

“…Thus, brain quantitative morphometric approaches using brain anatomical structural MRI examinations have often been employed in neuroscience investigations of neurotypical development [9][10][11][12][13][14], mental and developmental disorders, including schizophrenia [15,16], major depression [15,17], autism spectrum disorder [15,18], and attention-deficit/hyperactivity disorder [19,20]. However, except for relatively common diseases, such as Down syndrome [21,22] and Rett syndrome [23][24][25], brain morphology in most congenital genetic disorders has not been studied to date because it is difficult to collect many examples of the same rare disease in a single facility.…”