Neurobiologically-based treatments in Rett syndrome: opportunities and challenges

Figures & data

Figure 1. Model of neuronal pathology in Rett syndrome based on dendritic development in the prefrontal cortex. (a) During normal development, onset of MeCP2 expression coincides with early neuronal differentiation. Levels of MeCP2 function, depicted as intensity of blue label, increase steadily after afferents (e.g., monoamines) begin to influence cortical neuronal differentiation. Direct targets of MeCP2, such as BDNF, in conjunction with other synaptic signals have a particularly strong effect on the process of dendritic pruning. (b) Marked reduction in MeCP2 function and deficient afferent input in neurons carrying a MeCP2 mutated allele impairs appropriate dendritic expansion. The abnormality extends and worsens during dendritic pruning because of the abnormally high levels of MeCP2 targets (i.e., BDNF) and additional neurotransmitter disturbances (glutamate receptor activity). The ultimate neuronal phenotype is characterized by a smaller cell with markedly decreased MeCP2 expression and dendritic arborizations. RTT neurons carrying the normal allele are also affected. Because of decreased local (neighboring neurons with mutated allele) and distant (monoaminergic) synaptic signals, and secondary abnormalities such as increases in BDNF and glutamatergic activity, these neurons are unable to reach normal soma and dendritic size and remain as low-expressing (MeCP2^lo) cells. GFs: growth factors. Used with permission from Ref. [34].

Table 1. Drugs used in clinical trials for Rett syndrome by mechanism.

Drug	References
General effects
Creatine	[80]
EPI-743	[81] and ClinicalTrials.gov identifier NCT01822249
Folate/Betaine	[82]
Folinic acid	[83–87]
Ketogenic diet	[88]
L-carnitine	[89]
Lovastatin	ClinicalTrials.gov identifier NCT02563860
Naltrexone	[90]
Omega-3 fatty acids	[91–93]
Triheptanoin	ClinicalTrials.gov identifier NCT02696044
General synaptic regulators
Cerebrolysin	[94]
Fingolimod	ClinicalTrials.gov identifier NCT02061137
Glatiramer acetate	[95] and ClinicalTrials.gov identifiers NCT02153723, NCT02023424
IGF-1	[25,96] and ClinicalTrials.gov identifier NCT01777542
Trofinetide (NNZ-2566)	[97] ClinicalTrials.gov identifiers NCT01703533, NCT02715115
Neurotransmitter modulators
Bromocriptine	[98]
Desipramine	ClinicalTrials.gov identifier NCT00990691
Dextromethorphan	[99] and ClinicalTrials.gov identifier NCT01520363
Ketamine	ClinicalTrials.gov identifier NCT02562820

Table 2. Most common outcome measures used in clinical trials for RTT.

Type of outcome measure	Examples [original or RTT-specific reference]	Trials utilizing the outcome measure
Distinctive RTT symptoms and signs	Motor Behavioral Assessment (MBA) [107]	[25,80,82,89,90,97,103] ClinicalTrials.gov identifier NCT02715115
	Clinical Severity Scale [108,109]	[25,81,91–93,97,102] ClinicalTrials.gov identifiers NCT01253317, NCT01822249, NCT02023424
General neurologic and physical measures	Nonstandardized assessments of motor function and seizure frequency/severity [see trials]	[83,84,88,96,103] ClinicalTrials.gov identifiers NCT02023424, NCT02563860, NCT02696044
	Growth parameters [16]	[81,82] and ClinicalTrials.gov identifier NCT02023424
Specialized neurological measures	Vineland Adaptive Behavior Scales [110]	[90,97,99] and ClinicalTrials.gov identifiers NCT00593957, NCT01253317
	Hand Apraxia Scale [111]	[89,100,103]
Behavioral Instruments	Rett Syndrome Behavioral Questionnaire (RSBQ) [112]	[25,81] and ClinicalTrials.gov identifiers NCT01253317, NCT01777542, NCT01822249, NCT02562820,
	Anxiety, Depression, and Mood Scale (ADAMS) [26]	[25] and ClinicalTrials.gov identifier NCT01253317
CGI and VAS	Clinical Global Impression (CGI) Scale [113]	[96] [97,114] and ClinicalTrials.gov identifiers NCT01253317, NCT02715115
	Visual Analog Scale (VAS) [115]	[97] and ClinicalTrials.gov identifiers NCT01253317, NCT02715115
Laboratory and neurophysiologic measures	EEG and other neurophysiological measures [116]	[25,83,88,90,94,96,97,99,103,117] and ClinicalTrials.gov identifiers NCT01253317, NCT02023424, NCT02562820, NCT02563860, NCT01777542
	Plethysmography [118,119]	[25,88,90,97] and ClinicalTrials.gov identifiers NCT00990691, NCT02023424, NCT02562820, NCT02563860, NCT01822249, NCT01777542
	Blood-based oxidative stress markers [see trials]	[91–93,102] and ClinicalTrials.gov identifier NCT01822249
Quality of life measures	Pediatric Quality of Life Inventory (PedsQL) [120]	ClinicalTrials.gov identifiers NCT01822249, NCT02563860
	Overall Well-Being Index [121]	[89,103]

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