Synaptic Dysfunction and Neural Circuitry
Neuronal connection and communication are impaired in FXS conditions. In a normal developing brain, connections between the neurons—synapses—experience a process of maturation and regression in which unnecessary synapses are removed and functional ones enhanced. This process is deemed to be important in the formation of functional neural circuits. However, in FXS, because there is no FMRP, the cells cannot go through the process of synaptic pruning, and there is an excess of parasynaptic boutons or immature synapses. This overproduction is the formation of disconnection, that is, the formation of an abnormal neural connection that hinders the communication between neurons, which gives rise to cognitive deficits and behavioral problems linked to the syndrome.
These synaptic abnormalities have been well elucidated in studies involving mouse models of FXS. For instance, the absence of the FMR1 gene in Fragile X knockout mice shows increased density of the dendritic spines, which are the tiny extensions of the cell body of neurons where synapses are established, than normal genetic mice. These spines are long and thin, the same as immature synapses that are inefficient in signal transfer. It is suggested that this morphological abnormality plays a role in the learning and memory in FXS.
Furthermore, it is documented that FMRP is also involved in the regulation of several proteins that directly underlie the genetic code for synaptic plasticity, such as proteins that belong to the metabotropic glutamate receptor 5 (mGluR5) pathway. The abnormality of this pathway has been linked to FXS, and it has been demonstrated that overactivation of this pathway is especially detrimental. Under normal circumstances, activation of the mGluR5 results in the production of proteins, which are essential for the process of consolidation of synapses. However, when there is a lack of FMRP, this process becomes uncontrolled and results in oversynthesis of proteins and disorder of synapse.
Neurodevelopmental Trajectories in Fragile X Syndrome
Neurodevelopment in FXS differs from healthy neurodevelopment in several ways and is at least ten times slower as described above. Cognitive development in this group of patients appears to be characterized by age equivalence for the first few years with modest improvement near the age of two years, a decline in abilities in the subsequent two or three years, and then stability or even deterioration during the next several years of development. This developmental trajectory is associated with synaptogenesis progression and synaptic abnormalities in the absence of FMRP.
Children with FXS may have quite normal motor and adaptive development during the early stages of development. This is by far true, but as the subjects grow older, a lot of time is lagged, particularly in the areas of learning and social skills. These delays are usually brought on by a state of stagnation in the child’s mental development in which the mental age remains stagnant and does not advance with the chronological age. This stagnation in cognitive development is a result of the compromise of synaptic processes in the brain, as highlighted above in discussions.
It is, however, important to note that the rate of decline in cognition seems to differ in people with FXS differently, with some even showing faster decline rates than the rest. This variability is believed to depend upon several factors: the level of methylation present in the FMR1 gene, mosaicism, in which some cells in the body produce FMRP while others do not, and the quality of educational and therapeutic programs offered to the affected child.
Behavioral and Psychiatric Manifestations
Due to alterations in neurotransmitters—and particularly to the neurobiological changes observed in FXS—patients experience various behavioral and psychiatric symptoms. It often observed social isolation, giant avoidance, and problems in general interaction with peers, noted signs of social anxiety. Besides, there is a high rate of development of autism features in children, such as hand flapping and line following. These symptoms are likely to be attributed to the disruption of the neural networks through synaptic overproduction coupled with the inability to prune them out as is supposed to happen with the maturing brain.
Deficit of attention and hyperactivity are also observed in FXS, with more frequencies in the boys. These symptoms are thought to originate from impaired signal processing within the neural networks, which are involved with attention and executive control of behavior. In addition, such patients suffer from mood disorders like anxiety and depression in rather high proportions given the social impact of the disorder.
Findings on sex differences in affected individuals also present one of the peculiarities of FXS. It is established that the manifestation of the disease is different in boys and girls. Men inherited one X chromosome, and therefore, the effects of the FMR1 mutation are more conspicuous in the male gender. Males, as for their turn, have one X and one Y chromosome; however, some of the cells may have normal FMR1 gene copy, which is why they present a less severe clinical picture. This phenomenon known as X inactivation leads to a vast degree of variation in women with FXS ranging from slightly affected learning disability to severe cognitive disability.
