A marathon sleeper who got away left some clues for Emory and University of Florida scientists to follow. What they found could provide benefits for patients with the genetic disease myotonic dystrophy (DM) and possibly the sleep disorder idiopathic hypersomnia (IH).

The classic symptom for DM is: someone has trouble releasing their grip on a doorknob. However, the disease does not only affect the muscles. Clinicians have recognized for years that DM can result in disabling daytime sleepiness and sometimes cognitive impairments. At the Myotonic Dystrophy Foundation meeting in September, a session was held gathering patient input on central nervous system (CNS) symptoms, so that future clinical trials could track those symptoms more rigorously.

Emory scientists are investigating this aspect of DM. Cell biology chair Gary Bassell was interested in the disease, because it’s a triplet repeat disorder, similar to fragile X syndrome, yet the CNS mechanisms and symptoms are very different. In DM, an expanded triplet or quadruplet repeat produces toxic RNA, which disrupts the process of RNA splicing, affecting multiple cell types and tissues.

Rye at San Francisco myotonic dystrophy meeting. Photo courtesy of Hypersomnia Foundation.

Neurologist and sleep specialist David Rye also has become involved. Recall Rye’s 2012 paper in Science Translational Medicine, which described a still-mysterious GABA-enhancing substance present in the spinal fluid of some super-sleepy patients. (GABA is a neurotransmitter important for regulating sleep.)

In seven of those patients, his team tested the “wake up” effects of flumazenil, conventionally used as an antidote to benzodiazepines. One of those patients was an Atlanta lawyer, whose recovery was later featured in the Wall Street Journal and on the Today Show. It turns out that another one of the seven, whose alertness increased in response to flumazenil, has DM.

In an overnight sleep exam, this man slept for 12 hours straight – the longest of the seven. But an IH diagnosis didn’t fit, because in the standard “take a nap five times” test, he didn’t doze off very quickly. He became frustrated with the stimulants he was given and sought treatment elsewhere, Rye says. Lab Land doesn’t have all the details of this patient’s history, but eventually he was diagnosed with DM, which clarified his situation.

More recently, Rye and his team have treated a small number (3) of DM patients with GABA antagonists — flumazenil or clarithromycin — with positive effects on alertness. Rye is collaborating with Andy Jenkins and Gary Bassell at Emory, and Eric Wang, a DM expert at the University of Florida.

Rye presented their findings both at the Myotonic Dystrophy Foundation meeting and at the World Sleep Congress in October. It appears that the RNA splicing perturbations in DM affect GABA receptors, and the GABA-enhancing substance is present too. That may produce a “double whammy” of sleepiness, according to Wang and Bassell.

Could scientists find hints to the identity of the GABA-enhancing “sleepy stuff” in IH by studying DM? Rye says:

“Additional basic science findings further suggest that there is much to be gained from examining hypersomnia through the lens of other disorders, especially one like myotonic dystrophy, whose genetics is well understood and where the field of scientists working on it is well developed. It’s a wonderful leveraging opportunity for two communities to inform one another.”

With the goal of treating more patients, Bassell, Jenkins, Wang and Rye are continuing this line of research, with the support of the Marigold Foundation. Jenkins – an expert on GABA receptors – has previously collaborated with Rye to study IH. The University of Florida has a cluster of DM expertise, including Laura Ranum, Andy Berglund and Maurice Swanson as well as Wang.

Bassell and his postdoc Anwesha Banerjee are collaborating with Rye and Wang to test the effects of GABA modulators in a nervous system-only mouse model of DM. Another strategy is to test antisense-style treatments – see below. Jenkins is examining the roots of the sensitivity of DM patients’ cells to anesthetics, a known problem leading to complications with anesthesia. Lab Land plans to learn more in the coming year.

Additional notes:

*While antisense-style drugs have been developed against SMA (spinal muscular atrophy) and DMD (Duchenne muscular dystrophy), Ionis Pharmaceuticals, which specializes in this type of drug, has reported setbacks in clinical trials aimed at treating muscle symptoms in myotonic dystrophy. The myotonic dystrophy community is actively working on the nervous system aspects for which no treatment is approved.At the MDF meeting (video here), several patients said they had tried modafinil.

*In human patients, the muscle weakness in DM can drive sleep apnea – so the sleepiness can be complex. Bassell’s nervous system-only mouse model could be helpful in dissecting the contributions of different tissues to sleep problems.

*Japanese and Polish scientists have observed that erythromycin, a chemical relative of clarithromycin, is effective in a DM mouse model, although the mechanism may be different and erythromycin is known to have cardiac side effects.

Viewing Hypersomnias through the Lens of Myotonic Dystrophy

The improving the lives of people living with

Our DNA is the genetic code that our cells use to instruct them in how to make proteins, when and where to make them, and how much protein to make.

The code is contained in the specific order in which

Unrefreshing sleep despite long duration of their major sleep periods

DM1 has a known genetic cause, so it gives researchers a solid place from which to start unraveling the mystery of pervasive sleep in IH. Moreover, the key group of DM1 scientists is substantial, and animal models for DM1 exist. Therefore, this offers a wonderful leveraging opportunity for two disease communities to assist one another. And funding from the Marigold Foundation is making this opportunity a reality. In September 2017, Emory University (Drs. David Rye, Andrew Jenkins and Gary Bassell) and University of Florida (Drs. Eric Wang and Maurice Swanson) researchers began interdisciplinary, patient-centered, collaborative investigations of hypersomnia as seen through the lens of DM1. The knowledge to be gained promises to be substantial and directly relevant to the development of novel diagnostic approaches and treatments for idiopathic hypersomnia and related disorders.

What Have We Learned So Far?

In looking for biologies shared by IH and DM1 patients, researchers did not have to wander far. One node of commonality that was quickly appreciated was centered upon By Abigail Piccolo, BS, and David Rye, MD, PhD, Chairperson,

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