Bryant Irawan
Dr. Brutlag
BIOCHEM 158
Due April 08, 2013
Mendelian Disease Case Project 1. The genetic disease I have chosen is narcolepsy. The OMIM url can be found here: http://www.omim.org/entry/161400. 2. 1,2Narcolepsy is a neurologic sleep disorder characterized by excessive daytime drowsiness and the inability to properly regulate sleep cycles. Thus, narcoleptics experience REM sleep, the deepest stage of sleep when dreaming occurs, within five minutes of sleep onset. Narcoleptics may also experience cataplexy, sudden loss of muscle tone, when experiencing strong emotions including laughter, fear, excitement, etc. When waking up or during sleep onset, narcoleptics often experience sleep paralysis, a temporary state of complete loss of muscle control. Sleep paralysis occurs when the brain believes REM sleep is occurring even though one is already awake or just about to sleep so it is easy to see how narcoleptics who have trouble regulating sleep cycles also frequently experience sleep paralysis. Besides sleep paralysis, hallucinations are also common during waking up or sleep onset. For almost all cases, narcolepsy is caused by the lack of a brain neurotransmitter called hypocretin. The shortage then causes a shorter, improperly controlled sleep cycle. 3. Diagnosis of narcolepsy may seem simple enough because of its characteristic cataplexy symptom. However, while almost all cases of cataplexy are tied with narcolepsy, not all cases of narcolepsy are tired with cataplexy. In one study by Daly and Yoss (1959) that examined three generations of a family, out of the twelve definite cases of narcolepsy, only three displayed cataplexy.1 A more universal symptom of narcolepsy is the excess daytime sleepiness from incorrect sleep cycles caused by the shortage of hypocretin neurotransmitters. Two tests are commonly associated with narcolepsy: the multiple sleep latency test (MSLT) and polysomnogram (PSG)2. The former measures the extent of daytime sleepiness while the polysomnogram confirms that that patient quickly enters REM sleep after sleep onset. The MSLT measures the amount of time it takes for a person to fall asleep at different times of the day2. The PSG is an overnight test that measures several values including electrical brain activity, muscle movement, and optical movement. Because REM sleep is characterized by rapid eye movement and a distinct electrical brain activity pattern along with little to no muscle movement, the PSG can record the exact time when a sleeping subject experiences REM sleep. 4. To date, narcolepsy cannot be cured because the hypocretin shortage is thought to be irreversible2. Symptoms like excessive daytime drowsiness or cataplexy, however, can be controlled. For excessive daytime drowsiness, sleep paralysis attacks, and hallucinations, doctors usually prescribe central nervous system stimulants like modafinil and methylphenidate (similar to amphetamines)-these two drugs specifically have been approved by the FDA for narcolepsy treatment2. Several side effects exist so a behavioral change is often recommended including proper sleep hygiene such as a regular sleep schedule, adequate sleep to reduce sleep debt, avoiding caffeine and exercise before sleep, etc. For cataplexy treatment, tricyclics and selective serotonin and noradrenergic reuptake inhibitors antidepressants are used. Likewise, several side effects can occur. Safe administration of hypocretin is not yet possible. 5. Narcolepsy for dogs has been shown to be caused by a single gene mutation. In humans, there are several genetic loci that have been linked with narcolepsy. Nevertheless, the significant mutation responsible is a dominant, heterozygous mutation in the HCRT gene on chromosome 17q211. In Thannickal et al. (2000), human narcoleptics’ hypothalamuses were studied and 85 to 95% reductions in the number of HCRT neurons were found. This dramatic reduction, however, did not manifest in melanin-concentrating hormone neurons which are intermixed with HCRT cells1. The study concluded that the specificity of the reduction to only HCRT neurons and the presence of gliosis in the hypocretin cell region imply HCRT neuronal loss as the cause of narcolepsy. Another well studied gene that is linked to narcolepsy is HLA-DBQ1, which encodes for a protein that helps the body identify self-proteins and foreign proteins. Many variations of the gene exist to accommodate for a variety of foreign proteins, however, the variation HLA-DQB1*06:02 seems frequently connected with narcolepsy especially with African Americans, white Americans, and Japanese1,3. This explains why many patients first report seeing narcolepsy after an infection. Note that the infection does not cause narcolepsy; it is only a trigger. Resistance to narcolepsy through genetics has been shown with the presence of minor alleles of a SNP and a marker in the NLC1A gene on chromosome 21q221. A complete distribution of HLA-DQB1*06:02 is referenced below. 6. While there is abundant research taking place to expand the knowledge on narcolepsy, the diagnosis for the disease is already quite simple. Regardless of whether or not the subject has cataplexy, all untreated narcoleptics have excess daytime sleepiness and improper sleep cycle control. These two symptoms are both easily testable with MSLT and PSG, which are described above. Currently, this is the standard procedure for diagnosis in almost all sleep clinics2. 7. Narcolepsy is a heavily researched subject. While finding a complete cure for narcolepsy is daunting, there are already treatment options that can effectively control symptoms of narcolepsy such as modafinil. As mentioned before, however, there are abundant side effects.
In Fernandes et al. (2013), modafinil’s effect on emotional memory was tested using mice injected with several different dosages of modafinil. The mice went through a training session where an averse stressor was applied at a specific arm of a maze. Ten days later, the mice were retested to see if the % time spent in aversive arm increased. For a certain threshold of modafinil (above 32 mg/kg), the % time spent in the aversive arm more than doubled suggesting these mice had difficulty consolidating the emotional discriminative avoidance task. Hopefully, this study will push toward the use of behavioral treatment including maintaining a healthy sleep hygiene to curtail narcoleptic symptoms.
Works Cited:
1. http://www.omim.org/entry/161400
2. http://www.ninds.nih.gov/disorders/narcolepsy/detail_narcolepsy.htm
3. http://ghr.nlm.nih.gov/condition/narcolepsy
4. http://www.sciencedirect.com/science/article/pii/S0028390812003267
5. http://www.allelefrequencies.net/hla6003a_scr.asp?hla_selection=DQB1*06:02&hla_locus1=&hla_locus2=&hla_locus3=&hla_locus4=&hla_locus5=&hla_locus6=&hla_locus7=&hla_locus8=&hla_population=&hla_country=&hla_dataset=&hla_region=&hla_ethnic=&hla_study=&hla_sample_size=&hla_sample_size_pattern=&hla_sample_year=&hla_sample_year_pattern=&hla_loci=&hla_order=order_3 s