**4. How and/or why did the patient develop a circadian rhythm sleep-wake disorder? Which individuals are of greatest risk of developing a circadian rhythm sleep-wake disorder?**

#### **4.1 Advanced sleep-wake phase disorder (ASWPD)**

Genetic studies have shown possible links to mutations in the *PER2* and *CSNK1D* clock genes, both of which are inherited in autosomal dominant pattern [2, 3]. There is an estimated 1% prevalence, with males and females being equally affected. Older adults are more likely to have advanced tendencies. Other contributing factors include decreased responsiveness to evening light, and increased responsiveness to morning light, both of which can shift the sleep–wake cycle earlier than desired.

#### **4.2 Delayed sleep–wake phase disorder (DSWPD)**

The pathophysiology of DSWPD is multifactorial [2, 3] l. It is hypothesized that certain exogenous factors, such as increased exposure to evening light and greater sensitivity to evening light may play a role in development of DSWPD. Genetic factors may play a role, but their exact contribution is less understood than is the case for ASWPD.

DSWPD typically emerges during adolescence and can continue into adulthood. Males and females seem to be affected equally. Peak age appears to be 21 years old in males and 17 years old in females. There is a large variability in its reported prevalence, with population study estimates ranging from <1% up to 10% [1–3]. Patients with hepatic cirrhosis are also affected at much higher rates (33%).

#### **4.3 Irregular sleep-wake rhythm disorder (ISWRD)**

ISWRD is most commonly seen in individuals with neurodegenerative conditions, particularly those with Alzheimer's disease and late-afternoon sundowning [1–3]. It is also more common in those with traumatic brain injury, in children with developmental delay, in patients with schizophrenia, and particularly in patients who are institutionalized. It is hypothesized that intrinsic circadian dysfunction, coupled with decreased exposure to external synchronizing agents such as light and social activity, are factors in ISWRD.
