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