Research on the body’s internal clock is revealing how phase shift disorders may be physiological.

By Alaa El-Gendy, MD, MSc, FCCP

Many living organisms exhibit a circadian rhythm in their physiology and behavior. In humans, plasma melatonin, sleep, and the body core temperature show circadian rhythmicity, which is generated by an endogenous biological oscillator.1 While circadian rhythm is adjusted to 24 hours by the environmental light/dark cycle and social time cues, patients with circadian rhythm sleep disorders cannot synchronize their sleep/wake cycle to the desired time schedule and have difficulties in their social lives. Two major circadian rhythm disorders associated with insomnia are the underlying cause of sleep disruptions in such patients—delayed sleep phase syndrome (DSPS) and advanced sleep phase syndrome (ASPS).2-5

Alaa El-Gendy, MD, MSc, FCCP


The International Classification of Sleep Disorders (ICSD) defines the delayed sleep phase syndrome as a condition in which the major sleep episode is delayed in relation to the desired clock time.6 This causes symptoms of sleep onset insomnia or inability to wake up at a conventional time for school or work. Unlike jet lag and shift work, delayed sleep phase syndrome is a persistent condition. Typically, the patient does not attempt to sleep until late (between 2 AM and 6 AM) and awakens in the late morning or afternoon (10 AM to 2 PM). Patients with this disorder generally have difficulty with daytime functioning and excessive somnolence. These patients often try a variety of hypnotic medications or alcohol in an attempt to initiate sleep. Sleep architecture is generally normal if these individuals are allowed to follow their own uninterrupted sleep-wake schedule. Primary DSPS results from an unusually long circadian period due to abnormalities in the suprachiasmatic nucleus. DSPS accounts for 5% to 10% of insomnia patients in some sleep disorders centers.7 Onset occurs during childhood or adolescence, and there may be a history of DSPS in other family members. In some cases, the disorder is associated with depression.


Advanced sleep phase syndrome is the converse of DSPS—the patient goes to sleep in the early evening and wakes up earlier than desired in the morning (2 AM to 4 AM). If affected patients do not go to sleep at an early hour, they suffer from sleep disruption and daytime sleepiness. ASPS is frequently seen in the elderly and in post-menopausal women. It can be treated pharmacologically, with evening bright lights, or behaviorally with chronotherapy or free-running sleep. The basic mechanism is an inherent shortening of the endogenous circadian timing period. This disorder is distinguished from the early morning awakening seen with depression because sleep architecture is normal and does not exhibit the shortened REM latency and other REM sleep abnormalities that are seen in depressed patients.


Hypothalamic suprachiasmatic neurons have three parts that maintain inherent rhythmicities: a way to receive input from the environment to set the clock (light, temperature); the clock itself (a chemical timekeeping mechanism); and genes that help the clock control the activity of other genes. In the last few decades, scientists have discovered the genes responsible for running the internal clocks: period (per), clock (clk), cycle (cyc), timeless (tim), frequency (frq), doubletime (dbt), and others.

Genetic mutational studies using Drosophila fruit flies led to the identification of the period (Per) gene. It is the first essential component of the circadian oscillator, which was followed by the isolation of various clock-relevant genes not only from Drosophila, but also from various species including mammals.8-10 Clock is a member of the basic helix-loop-helix (bHLH)-PAS family of proteins. PAS is made of three proteins: Drosophila period (PER), aryl hydrocarbon nuclear translocator (ARNT), and Drosophila single-minded protein (SIM). Clock is a transcription factor that, when partnered with BMAL1 (another bHLH protein), binds DNA to stimulate the expression of period proteins (PER1 and 2) and the cryptochromes (CRY1 and CRY2). Period proteins and the cryptochromes suppress the transcriptional activity of Clock-BMAL1, thus forming a negative feedback loop. Clock mutations resulted in a long free-running period and were mapped to the midportion of mouse chromosome 5 (a region of conserved synteny with human chromosome 4).11,12 By studying a single nucleotide polymorphism located in the 3′ flanking region of the human Clock gene, it was shown that subjects carrying one of the two Clock alleles, 3111C, had lower Horne-Ostberg scores and a 10- to 44-minute delay in preferred timing for activity or sleep episodes.13 Until recently, the role of circadian clock genes in human sleep disorders was unclear. It has been suspected that variations in the expression of these genes result in alteration of the circadian period, and may account for individual differences in sleep and arousal.

Recently, genetic contributions to the pathogenesis of DSPS and ASPS have been suggested by clinical genetic studies. In Drosophila and mouse models, long period mutants are generally phase-delayed with respect to an entraining light-dark cycle, whereas short period mutants are usually phase-advanced.


In 1999, Louis Ptáãek’s research group at the University of California, San Francisco reported familial advanced sleep phase syndrome (FASPS). The disorder was characterized by a lifelong pattern of sleep onset around 7:30 PM and offset around 4:30 AM. Among three lineages, 29 people were identified as affected with FASPS, and 46 were considered unaffected. The pedigrees demonstrated FASPS to be a highly penetrant, autosomal dominant trait.14 Two years later, Ptáãek’s group published their results of genetic sequencing analysis on a family with FASPS. They took a cue from research on the Per mutations in Drosophila?9 and mouse10 models, which produced short-day mutants and were predicted to produce a phase advance in humans.15 With this in mind, they quickly found that the sequencing of the hPer2 gene revealed a serine-to-glycine point mutation in the CK1e binding domain of the hPER2 protein.16 In 2005, they reported discovery of a different mutation causing FASPS. The CK1d was involved, demonstrating an A-to-G missense mutation that resulted in a threonine-to-alanine alteration in the protein.17 The evidence for both of these reported causes of FASPS is strengthened by the absence of such mutations in all tested control subjects.16,17 Additional genes may be involved, since for some FASPS families, there is no link to the hPER2 locus.

Unlike ASPS, DSPS, found more frequently in young adults, is associated with delayed bedtime and delayed wake time. DSPS has been proposed to be associated with structural polymorphisms in the human period-3 (hPER3) gene.18,19 This is the first study analyzing the hPER3 gene for polymorphisms in circadian rhythm sleep disorders. The findings suggest that the H4 haplotype of the hPER3 gene may confer susceptibility to DSPS in 15% of affected people. DSPS also tends to run in families.20 There have been several reported cases of DSPS and non-24-hour sleep-wake syndrome developing after traumatic head injury.21,22


DSPS and ASPS are diagnosed by clinical interview, actigraphic recordings over several days documenting the characteristic sleep schedule, and/or sleep log.


In mild cases, DSPS can be controlled by waking up and going to bed 15 minutes earlier every day until the desired sleep schedule is achieved. More severe cases can be treated by light therapy, chronotherapy, melatonin, ramelteon, vitamin B12, modafinil, and trazodone.

Two possible treatments for ASPS are bright-light therapy and administration of exogenous melatonin.


Additional studies are currently taking place. When genetic factors are identified, valuable insights into the pathogenesis of ASPS and DSPS will help in developing therapeutic strategies to treat patients with these disorders.

Alaa El-Gendy, MD, MSc, FCCP, is medical director at Florida Lung & Sleep Associates, Lehigh Acres, Fla.


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