Sleep-wake dysregulation and altered melatonin in neurofibromatosis type 1

Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder resulting from pathogenic variants in the NF1 gene. Preclinical studies suggest the NF1 gene regulates sleep and circadian processes, yet objective human data are limited. Characterizing sleep disturbances, sleep-related biomarkers, and their relationships to neurodevelopmental outcomes, may identify potential novel therapeutic targets in children with NF1. This study aimed to compare sleep-wake profiles, circadian rhythmicity, and melatonin production in children with NF1 compared to typically developing controls, and to examine relationships between sleep outcomes, cognition, and behavior.

In this cross-sectional study, children aged 6-16 years with NF1 were recruited and compared to controls. Actigraphy data over 1 week were used to derive nine sleep-wake rhythm variables. Overnight urinary 6-sulfatoxymelatonin served as marker of melatonin secretion. Neuropsychological and subjective assessment of sleep were also examined.

Compared to controls, children with NF1 had lower 6-sulfatoxymelatonin secretion, which was significantly associated with significantly longer sleep latency. Children with NF1 also had greater sleep irregularity and reduced total sleep time. Cluster analysis revealed four distinct sleep profiles in NF1: (1) delayed sleep onset, (2) night-wakers, (3) generalized sleep difficulties, and (4) normal sleep patterns. Greater sleep disturbance was associated with lower adaptive functioning, elevated behavioral difficulties, and poorer cognition in NF1.

The current findings highlight the importance of sleep assessment in this group and suggest that altered sleep and circadian regulation are related to the broader neurodevelopmental phenotype in NF1.