Viewing Hypersomnias Through the Lens of Myotonic Dystrophy

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The Hypersomnia Foundation is excited to welcome the Marigold Foundation as a community partner in our commitment to improving the lives of people living with idiopathic hypersomnia and related sleep disorders. The Marigold Foundation is committed to the development of meaningful treatments for orphan diseases, particularly myotonic muscular dystrophy. So how and why is myotonic dystrophy relevant to the hypersomnia community? Here, Abigail Piccolo and Dr. David Rye explain.

What Is Myotonic Dystrophy?

Myotonic Dystrophy (see Note 1) is traditionally taught to be a disease of muscle in which the muscles can contract but have a difficult time relaxing. Over time there is also loss of muscle mass – or, muscular dystrophy. In the field of medicine, it is referred to as dystrophia myotonica and is abbreviated as DM. DM occurs in two forms, both of which are caused by “triplet repeat” gene mutations that result in abnormal expansion in one’s DNA (see Note 2). The DM Type 1 (DM1) expansion occurs on Chromosome 19 and the DM Type 2 (DM2) expansion occurs on Chromosome 3. This article concerns itself almost entirely with DM1 and its potential relevance to the study of idiopathic hypersomnia (IH).

Symptoms of DM1 usually emerge in young adulthood. Symptoms can be present at birth (congenital forms), or emerge later in childhood (juvenile onset forms). Weakness is evident in muscles of the hands, feet, neck, and face. This weakness worsens with age, and patients also develop an inability to relax their muscles. They might pick up an object, only to struggle to relax their muscles to release the object. Many patients also develop weakness in involuntary muscles, such as those that assist in breathing, or those necessary to swallow and move food along the complicated path of digestion. DM1 is a degenerative disease, and there is no cure or even a treatment to slow its progression. Patients who are diagnosed earlier can begin treatments to manage symptoms and to reduce complications, and thus, to improve their quality of life.

Note 1:  “Myo-” = muscle. “-tonic” = contraction. Myotonic refers to constant contraction of muscles, or an inability to relax muscles at will. “Dys-“ = abnormal. “-trophy” = growth. Dystrophy refers to abnormal growth, specifically degeneration in this instance.

Note 2: What is a triplet repeat expansion?

  • 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 nucleotide bases occur (scientists abbreviate these nucelotides as A, T, C and G).
  • Sometimes a “triplet” of bases (in DM1, the triplet repeat is “CTG”) are incorrectly repeated in a section of the DNA, which in turn results in mistakes in the proteins that they code for.  
  • With each successive generation, the repeats expand in length. With a higher number of repeats, the disease begins to emerge at a younger age, and is typically more severe.

What Does Myotonic Dystrophy Have to Do with Idiopathic Hypersomnia?

Myotonic dystrophy is of great interest to IH sleep researchers because DM1 patients experience symptoms that are striking in their similarity to those of IH patients. Most DM1 patients report somnolence, the feeling of excessive sleepiness or drowsiness, and other symptoms familiar to IH subjects such as:

A Different Diagnosis: Does This Mean I Have Myotonic Dystrophy?

Just because myotonic dystrophy patients experience somnolence does not mean that IH patients have myotonic dystrophy. The somnolence and excessive sleep common to both IH and DM1 could lead one to refer to one disease as a “phenocopy” of the other. Phenocopy is a term used to refer to a disease whose pattern of symptoms resembles that of another disease entity that has otherwise been given a unique “name” (which carries with it a presumption that it results from a different cause).

Alternatively, when patterns of sleep are similar, it is possible that the ”causes” share something in common. A phenocopy can be very helpful to researchers in search of a “cause” to their disease of interest. In the case of idiopathic hypersomnia, whose cause remains unknown, a disease with similar symptoms, such as DM1, can provide valuable clues as to what ultimately “causes” IH. Consider the following example:

Sarah and John both own car washes. One day, the cars that come out of Sarah’s car wash still have soap on them. An indicator on her car wash shows that something is wrong with the rinsing system. She investigates the problem to find that the rinsing nozzle is broken, and she is able to fix it.

Soon after, the cars coming out of John’s car wash still have soap on them, and he needs to investigate the problem. Unfortunately, his car wash does not have an indicator system, and it would be difficult to take all the pieces apart to find the exact problem. He talks to Sarah, since she had a similar problem. Sarah recommends looking at the rinsing mechanism first. John discovers that his hose for the rinsing nozzle was disconnected. It took him much less time to find the problem because he knew where to look, with Sarah’s help.

This example helps one appreciate how a study of DM1 might help researchers pinpoint the causes of unrefreshing sleep, sleep drunkenness, “brain fog”, and somnolence in IH. Examining each part of the sleep system in IH for the source of the problem would be time and cost intensive because sleep is such a complex trait – i.e., one that is affected by many environmental and genetic factors. So, if two disease processes result in a similar pattern of symptoms – that is, if they are phenocopies – their causes might also be similar.

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 GABA receptors. GABA receptors are found on neurons in the brain, and when activated, they cause a reduction in neuronal signaling, like an “off” switch that dampens conscious awareness and promotes sleep. Emory University scientists have previously found that many IH patients harbour a still unknown, naturally occurring substance in their cerebrospinal fluid (CSF) that enhances GABA receptors, essentially allowing for more efficient flipping of “off” switches in the brain (D. Rye et al., Science Translational Medicine, 2012). Enhancement of GABA receptors was further implicated when some IH patients were treated successfully with flumazenil, a drug that blocks modulators that activate GABA receptors. As detailed in previous SomnusNooze articles, flumazenil effectively prevents the flipping of so many of the brain’s switches to the “off” position in many patients.

By serendipity, one of the patients in the original 2012 study, whose somnolence was dramatically reversed by flumazenil, was later diagnosed with DM1. In CSF samples from each of three (3) other DM1 patients suffering from profound hypersomnia, enhancement of GABA receptor activity was also found, and treatment with the receptor antagonists clarithromycin and flumazenil yielded positive effects on alertness and “brain fog” in two of them. Work in part from the University of Florida suggests that DM1 genetic disruptions alter GABA receptor function independent of changes detectable in CSF, thereby rendering the GABA system even more susceptible to enhancement. Dr. Rye presented these exciting preliminary findings at both the September International Myotonic Dystrophy Consortium in San Francisco and at the October World Sleep Congress in Prague.

These preliminary findings already point to a plausible explanation for IH and DM1 sharing pervasive sleepiness in common, and reinforces the potential rewards that can emerge in studying phenocopies. We look forward with great hope to what further knowledge this Marigold Foundation-funded collaboration may unearth, and how it may fuel new treatments for both diseases.

By Abigail Piccolo, BS, and David Rye, MD, PhD, Chairperson, HF Scientific Advisory Board

For further reading, see “The Journey of a Marathon Sleeper” from the December 2017 edition of Lab Land – The Emory Health Sciences Research Blog.

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