Advanced sleep phase disorder

Advanced sleep phase disorder (ASPD), also known as the advanced sleep-phase type (ASPT) of circadian rhythm sleep disorder or advanced sleep phase syndrome (ASPS), is a condition in which patients feel very sleepy and go to bed early in the evening (e.g. 6:00–8:00 p.m.) and wake up very early in the morning (e.g. around 3:00 a.m.).

Symptoms
People with ASPD are unable to stay awake until their desired bedtime and unable to stay asleep until their desired waking time. They will complain to a sleep clinician of early morning insomnia and falling asleep early in the evening. When someone has advanced sleep phase disorder their melatonin levels and core body temperature will cycle hours earlier than an average person. These symptoms must be present for at least three months in order to be correctly diagnosed.

Epidemiology
ASPD is a rare disorder. It affects both men and women equally and has been determined to have a strong genetic link with 40–50% of people related to someone with ASPD having it themselves. As stated below, several genes have been discovered to have links with this syndrome and the body's circadian rhythms. Although it can be impairing, the syndrome is not necessarily unhealthy; most people don't seek help unless it starts to severely impact their social life.

Treatment
Once diagnosed, ASPD can be treated with bright light therapy in the evenings or behaviorally with chronotherapy. Unlike other sleep disorders, ASPD does not disrupt normal functioning at work during the day and the patient does not complain of excessive daytime sleepiness. If their ASPD is causing people to lose out on evening activities, including putting their own normal children to bed, then they can force themselves to stay up later than their circadian rhythm wants them to. A sufferer of ASPD will still wake up very early and if this cycle continues it can lead to chronic sleep deprivation and other sleep disorders.

Familial advanced sleep phase syndrome
In 1999, Louis Ptáček's research group at the University of California, San Francisco reported findings of a human circadian rhythm disorder showing a familial tendency. The disorder was characterized by a lifelong pattern of sleep onset around 7:30 p.m. and offset around 4:30 a.m. Among three lineages, 29 people were identified as affected with this familial advanced sleep-phase disorder (FASPD), and 46 were considered unaffected. The pedigrees demonstrated FASPD to be a highly penetrant, autosomal dominant trait.

Two years after reporting the finding of FASPD, Ptáček's and Fu's groups published results of genetic sequencing analysis on a family with FASPD. They genetically mapped the FASPD locus to chromosome 2q where very little human genome sequence was then available. Thus, they identified and sequenced all the genes in the critical interval. One of these was Period2 (Per2). Sequencing of the hPer2 gene revealed a serine-to-glycine point mutation in the CKI binding domain of the hPER2 protein that resulted in hypophosphorylation of Per2 in vitro.

In 2005, Fu's and Ptáček's labs reported discovery of a different mutation causing FASPD. This time, CKIδ was implicated, demonstrating an A-to-G missense mutation that resulted in a threonine-to-alanine alteration in the protein. The evidence for both of these reported causes of FASPD is strengthened by the absence of said mutations in all tested control subjects and by demonstration of functional consequences of the respective mutations in vitro. Fruit flies and mice engineered to carry the human mutation also demonstrated abnormal circadian phenotypes although the mutant flies had a long circadian period while the mutant mice had a shorter period. The differences between flies and mammals that account for this difference are not known. Most recently, Ptáček and Fu reported additional studies of the human Per2 S662G mutation and generation of mice carrying the human mutation. These mice had a circadian period almost 2 hours shorter than wild-type animals. Genetic dosage studies of CKIδ on the Per2 S662G mutation revealed that CKIδ is having opposite effects on Per2 levels depending on the sites on Per2 that CKIδ is phosphorylating.