Twenty‐four‐hour motor activity and body temperature patterns suggest altered central circadian timekeeping in Smith–Magenis syndrome, a neurodevelopmental disorder

Abstract

Smith-Magenis Syndrome (SMS) is a contiguous gene syndrome linked to interstitial microdeletion, or mutation of RAI1, within chromosome 17p11.2. Key behavioral features of SMS include intellectual disability (ID), sleep-disturbances, maladaptive, aggressive and self-injurious behaviors, hyperactivity and sudden changes in mood. A distinguishing feature of this syndrome is an inverted pattern of melatonin characterized by elevated daytime and low nighttime melatonin levels. Since the central circadian clock controls the 24-hour rhythm of melatonin, we hypothesized that the clock itself may contribute to the disrupted pattern of melatonin and sleep. In this report, 24-hour patterns of body temperature, a surrogate marker of clock-timing, and continuous wrist activity were collected to examine the links between body temperature, sleep behavior, and the circadian clock. In addition, age-dependent changes in sleep behavior were explored. Actigraphy-estimated sleep time for SMS was one hour less than expected across all ages studied. The timing of the 24-hour body temperature (Tb-24) rhythm was phase advanced, but not inverted. Compared to sibling (SIB) controls, the SMS group had less total night sleep, lower sleep efficiency, earlier sleep onset, earlier final awake times, increased waking after sleep onset (WASO), and increased daytime nap duration. The timing of wake onset varied with age, providing evidence of ongoing developmental sleep changes from childhood thru adolescence. Clarification of the circadian and developmental factors that contribute to the disrupted and variable sleep patterns in this syndrome will be helpful in identifying more effective individualized treatments.

Smith‐Magenis syndrome: Clinical and behavioral characteristics in a large retrospective cohort

“…SMS is associated with a specific sleep disturbance: night‐time and early morning awakening and shortened sleep cycles. Sleep disturbances have been linked to an inverted melatonin release pattern, which disrupts the sleep–wake cycle (melatonin cycle) 10‐12 . A combination of oral melatonin at bedtime and betablockers at the morning has been proposed to improve sleep cycle and, indirectly, behavioral disorders 13 .…”

Tasimelteon safely and effectively improves sleep in Smith–Magenis syndrome: a double-blind randomized trial followed by an open-label extension

“…Sleep for these patients is characterized by difficulty sleeping at night and resultant excessive daytime sleepiness [9][10][11][12][13]. Individuals with SMS have decreased total night sleep, lower sleep efficiency, earlier sleep onset, final sleep offset, and increased waking after sleep onset compared to healthy individuals of the same age [14]. During these nighttime awakenings, individuals with SMS can pose a significant danger to themselves and disrupt the sleep of their family members.…”

De Novo KAT5 Variants Cause a Syndrome with Recognizable Facial Dysmorphisms, Cerebellar Atrophy, Sleep Disturbance, and Epilepsy

“…60 SMS due to deletions of 17p11.2 or RAI1 variants is associated with a recognized circadian sleep disorder characterized by an advanced sleep phase and inverted melatonin secretion profile. 61,62 Autosomal dominant mental retardation type 1 (MIM: 156200) is caused by variants in MBD5 (MIM: 611472) that encode Methyl-CpG-binding domain protein 5, which is part of a polycomb repressive complex that deubiquitinates a lysine of histone H2A. Interestingly, disturbed PER1 levels were noted with both MBD5 mutations and with SMS.…”