Neurodevelopmental disorders Flashcards
Monogenetic ND disorders
What method is used to identify causal mutations in children with sporadic developmental delay/intellectual disability?
Genome sequencing, specifically targeting the exome
Traditionally, diagnosis relied heavily on observing symptoms and clinical evaluations. However, with advancements in genetic testing, particularly exome sequencing, researchers can now identify specific gene mutations associated with these disorders. This involves sequencing the coding regions of a patient’s DNA and comparing it to their parents’ DNA to identify new mutations present only in the child.
What causes Fragile X syndrome?
Fragile X syndrome is a trinucleotide repeat expansion disorder caused by an abnormal expansion of a specific three-nucleotide sequence (CGG) within the FMR1 gene.
The FMR1 gene is divided into exons and introns. A region in the 5 prime untranslated region of the gene contains a CGG repeat. The number of repeats determines whether an individual will have Fragile X syndrome.
Normal individuals= 29–40 CGG repeats.
Premutation but unaffected= 55–200 CGG repeats
FXS=more than 200 CGG repeats
How does the expansion of the CGG repeat lead to Fragile X syndrome?
Full expansion causes methylation of the gene, which silences the gene and prevents the production of FMRP, a protein that’s important for brain development.
What is the role of FMRP in neuronal activity?
FMRP is thought to regulate protein synthesis by shutting down translation after synaptic firing through binding to mRNAs
Plays a crucial role in learning and memory. In FXS, no FMRP= too much protein synthesis at the synapse, disrupting normal neuronal communication and contributing to the observed cognitive and behavioral impairments.
What are the potential therapies for Fragile X syndrome?
Potential therapies include drugs that antagonize mGluR5 and demethylation of the FMR1 gene.
How do mutations in the MeCP2 gene lead to Rett syndrome?
MeCP2 is a DNA-binding protein that acts as a transcriptional repressor. It binds to methylated DNA and recruits a co-repressor complex.
Mutations in the MeCP2 gene disrupt the protein’s ability to bind to methylated DNA or recruit the NCoR/SMRT co-repressor complex. This leads to the failure of MeCP2 to repress transcription and widespread changes in gene expression.
What evidence suggests that Rett syndrome is potentially curable?
Describe the key experimental evidence that supports the reversibility of Rett syndrome in a mouse model.
Studies using a mouse model with a reversible MeCP2 gene inactivation have shown that restoring MeCP2 expression after symptom onset can reverse the neurological phenotypes.
The reversibility of Rett syndrome in mice was demonstrated by inserting a “stop cassette” into the MeCP2 gene, causing the development of Rett-like symptoms. Upon removal of the stop cassette, MeCP2 expression was restored, leading to a significant reversal of neurological symptoms, even in older mice. This suggests that the disorder results from a lack of MeCP2 function rather than irreversible developmental defects.
What are the common features of genes implicated in neurodevelopmental disorders?
Studies using exome sequencing have revealed that mutations in over 100 different genes can cause neurodevelopmental disorders. Many of these genes encode proteins involved in synaptic function, highlighting the importance of proper synaptic communication for normal brain development.
What is Rett Syndrome and how does it differ from Fragile X Syndrome?
Rett syndrome primarily affects girls and is also caused by a mutation on the X chromosome, specifically in the MECP2 gene. Unlike Fragile X, where the gene is silenced, Rett syndrome results from mutations that alter the function of the MeCP2 protein. This protein acts as a transcriptional regulator, influencing the expression of other genes important for brain development.
Describe the “trio” approach used in exome sequencing studies to identify causal mutations for neurodevelopmental disorders.
The “trio” approach involves sequencing the exomes of both parents and their child. Researchers look for mutations present in the child but absent in both parents, suggesting a de novo mutation that potentially correlates with the disorder.
What is the significance of the probability line in the chromosome map showing genes associated with neurodevelopmental disorders?
The probability line on the chromosome map indicates the level of confidence that a specific gene mutation is causally linked to a neurodevelopmental disorder. Genes above the line have a higher probability of being causally implicated.
What is the primary reason that current drug therapies for Fragile X syndrome have been unsuccessful?
Current drug therapies targeting Fragile X syndrome have been unsuccessful mainly due to their inability to specifically address the underlying cause: the absence of FMRP. Approaches like receptor antagonism have proven ineffective, and while demethylation strategies are promising, they face technical challenges.
How does X-inactivation contribute to the mosaic pattern of cells observed in females with Rett syndrome?
In females with Rett syndrome, one X chromosome in each cell is randomly inactivated early in development. Since females inherit one normal and one mutated MeCP2 gene, this results in a mosaic of cells: some expressing the functional MeCP2 protein and others expressing the mutated version. This mosaicism contributes to the variable and often milder symptoms in females compared to males who only have one X chromosome.
What is the main challenge in translating the promising results of gene therapy for Rett syndrome in mice to human treatments?
The main challenge in translating promising gene therapy results from mice to humans lies in efficiently delivering the therapeutic gene to a sufficient number of brain cells. The current AAV9 viral vectors used in clinical trials only reach a small percentage of neurons. Developing vectors with broader brain cell tropism is crucial for achieving a more impactful therapeutic outcome in humans.
