Smith-Magenis Syndrome

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Five-year-old Beth has Smith-Magenis syndrome (SMS). SMS is caused by a deletion mutation of chromosome 17. Along with facial and skull abnormalities, which her parents first noticed when she was just a baby, Beth has several cognitive and behavioral problems, including mental retardation, tantrums, hyperactivity, attention deficit, and self-injury. She also has a severe sleep disturbance.

Beth’s sleep pattern is very different from that of a typical child her age. She awakens at least once every night and then has a hard time getting back to sleep. She is usually awake to stay by 4 or 5 a.m. As a result, she feels extremely sleepy during the day, and has sudden “sleep attacks.” Beth’s tiredness contributes to her cognitive and behavioral difficulties. However, new research may soon help Beth and others with SMS get the sleep they need.

Dr. Hélène De Leersnyder of Necker-Enfants Malades Hospital in Paris became interested in the sleep disturbance aspect of SMS when she attended a meeting of parents of children with SMS. She was intrigued by the parents’ unanimous reports of their children’s sleep troubles. De Leersnyder and some of her colleagues decided to see if they could discover the cause of the SMS sleep disturbance.

The researchers found that individuals with SMS have an “inverted circadian rhythm of melatonin.” In other words, the timing of the rise and fall in their levels of the hormone melatonin is the opposite of what it should be. In an individual with a normal sleep cycle, levels of melatonin fluctuate in a predictable way—that is, melatonin peaks at night, causing drowsiness, and then subsides, reaching its lowest level in the middle of the day. But in people with SMS, melatonin levels are lowest at night and highest during the day. The results of this study were presented at the annual meeting of the American Society of Human Genetics in 1999.

Next De Leersnyder turned her efforts to developing an effective treatment. With the goal of normalizing the sleep cycles of children with SMS, De Leersnyder’s group gave the children two medications: a drug called acebutolol in the morning and a melatonin pill in the evening. Although the potential benefit of taking melatonin is easy to understand, the reason for administering acebutolol is less obvious. The natural secretion of melatonin in the body is controlled by the sympathetic division of the autonomic nervous system, which uses the neurotransmitter norepinephrine. Acebutolol is a type of drug called a selective beta-adrenergic antagonist, meaning that it blocks the interaction of norepinephrine with certain of its membrane receptors. Thus, acebutolol suppresses the secretion of melatonin.

The results of De Leersnyder’s dual-medication tactic, reported in 2003, were very promising. Not only did the combination of drugs help the children with SMS have a more normal sleep cycle, but it also lessened the severity of their behavioral problems and improved their ability to concentrate. There are other selective beta-adrenergic antagonists besides acebutolol, and now De Leersnyder is testing those on children with SMS, along with melatonin, to see if any of them can produce even greater improvement. Although beta-adrenergic antagonists and melatonin can’t cure SMS, they may help reduce some of the symptoms of children like Beth.

Questions

  1. What are the consequences of constantly interrupted sleep for an individual who does not have SMS? How might this help explain why normalizing the sleep cycle helped with some of the cognitive and behavioral problems of the children with SMS?

  2. Does the sleep disturbance in SMS bear any similarity to better-known problems, such as jet lag and seasonal affective disorder (SAD)? Explain.

  3. SMS has an autosomal dominant inheritance pattern, but neither of Beth’s parents has SMS. How do you think Beth acquired SMS?

Assignments

  1. Review the definition of a syndrome. How does the term apply to Beth’s condition?

  2. What is a deletion mutation, and how does such a mutation occur? The relationship between the deletion mutation that causes SMS and the abnormal pattern of melatonin secretion is still not clear. Speculate on possible connections. Why won’t medications like those being studied by De Leersnyder cure SMS?

  3. Find out more about circadian rhythms. Do organisms other than humans have circadian rhythms? Besides sleep, describe some of the other activities in the human body that follow a circadian rhythm. Do you think circadian rhythms are important for maintaining homeostasis? Why or why not?

  4. Review the role of the autonomic nervous system in the body. List some of the effects of sympathetic activation.

  5. Investigate SMS, reporting on (1) its prevalence, (2) how it is diagnosed, (3) its common clinical features, and (4) the challenges faced by parents of children like Beth.

  6. Melatonin is thought to be important not only in our sleep cycle, but also in the timing of the onset of puberty. What is the source of melatonin in the body? Exposure to light is responsible for regulating the normal fluctuations in melatonin levels. Briefly describe the mechanism involved. Could the modern-day use of artificial indoor light (including that from television and computer screens) be affecting the age of human sexual maturity? Explain.

References

http://www.geneclinics.org/profiles/sms&id=8888888&key=r5uHMS56EHeaU

http://web.sfn.org/content/Publications/BrainBriefings/bio_clocks.htm

http://web.sfn.org/content/Publications/BrainFacts/index.html

http://health.howstuffworks.com/sleep.htm

http://www.orpha.net/data/patho/GB/uk-SMS.pdf

http://www.newscientist.com/article.ns?id=dn6081

Young, M. W. 2000. The tick-tock of the biological clock. Scientific American 282:64–71.