Genetic Testing as it Relates to Rare Phenotypes of Epilepsy I think that the body of knowledge in the area of genetic testing for rare diseases is one of the most fascinating scientific breakthroughs in my lifetime. Just imagine how many people will be helped with early diagnosis and treatment. Patients can finally bypass the barrage of doctors, testing, medications and misdiagnoses. Epilepsy is a "rare disease" that has become of great interest to me for personal reasons. Not only because a friend of mine in summer camp would have Tonic-Clonic "grand mal" seizures in the middle of the night; but also because of an unpleasant experience I recently went through that mimics a modal phenotype of epilepsy. From what I gather, some epilepsy phenotypes are particularly "rare." What I find interesting is how whole genome sequencing can actually help researchers identify the obscure subtypes that puzzle practitioners. Myoclonus About a year ago a neurologist reviewed a video of me taken by my husband. I was experiencing severe "convulsions," for lack of a better word, that doctors referred to as "seizures." While epilepsy wasn't a definitive diagnosis, the sleep medicine specialist suspected that I had a subtype of epilepsy referred to as "myoclonic seizures." The myoclonus I experienced would occur every time I started to nod off. Suddenly there would be violent, jolting muscle spasms making me involuntarily groan from rapid stomach contractions that forced air past my vocal chords. Shoulders, stomach, back, head, neck, face muscles and legs were the most affected areas by the convulsions. The contractions were so violent that it felt as if my joints would dislocate. It would sometimes be accompanied by an insatiable restlessness that defies description. My face would contort, head would swivel side to side, and my legs would extend and elevate. I had heard of tardive dyskinesia and movement disorders, but never imagined just how bad they can be to experience. Apart from the pain and anguish, the episodes are embarrassing and can happen in public places. The myoclonus took a toll on my wellbeing, affecting different aspects of life. It inhibited sleep or rest; and led to social isolation.
Extrapyramidal symptoms It turns out that it is far more likely to be medication-induced "extra-pyramidal symptoms" of a prescribed pain medication called buprenorphine--or perhaps the med's contraindication with venlafaxine. Both medications affect serotonin levels in the brain. I'm writing about this myoclonic syndrome because there seems to be so little information about the type I suffered from. It's very "non-specific." Buprenorphine is being used off-label by my doctor for the treatment of acute pain. I found no literature online that named buprenorphine specifically as it relates to extrapyramidal symptoms. Indirectly, however, the medication is generally implicated as it falls under the category of opioids. To confuse matters further, extrapyramidal symptoms are not limited to opioids, but rather a wide spectrum of medications, including antidepressants, mood stabilizers and neuroleptics. If you are on a number of medications, sometimes problem-solving can be complex. So maybe this post will serve to help someone who is taking similar medication. First signs The myoclonus slowly emerged around the same time that I was switched from morphine-sulphate IR onto buprenorphine. But it was very subtle in the beginning so I didn't make the connection. I experienced short, mild shudders whenever I became tired or began to nod-off. However, over time the myoclonus became gradually worse until it was severe and debilitating. Rapid reversal I take the medication as needed, but it just so happened that I didn't take it for a couple weeks. It occurred to me that I hadn't experienced the convulsions for a while. In fact, they seemed to disappear completely. The first time I continued the medication after the two-week hiatus, I experienced violent myoclonic episodes in the evening. Through trial and error, process of elimination and deductive reasoning, the medications, I was able to establish that the seizures would occur for 48 hours after a single dose on the first day. Then they would quickly subside.
If you are in a similar situation and experiencing these forms of convulsions/seizures, speak to your prescribing doctor. In my case, the pain medicine physician has no knowledge of myoclonus, and never even heard of extrapyramidal symptoms from buprenorphine. Despite my empirical discovery, he still maintains that the medication is not the cause of the myoclonus. This type of myoclonus would fall under the category of rare, "non-epileptic paroxysmal movement disorders." Rare Disease identification of Myoclonic epilepsy While my own case is probably not within the area of epilepsy, myoclonic seizures are. In my attempt to figure out my own problem, I found that there is a body of genetic research in myoclonic epilepsy. In Nature's Journal of Human Genetics, a published research abstract cited a breakthrough in the genetic sequencing. According to the abstract, standard genetic testing came up negative. However, whole genome sequencing long-reading led the researchers to hone in on a mutation associated with neuronal ceroid lipofuscinosis, which is a rare disease in which myoclonic epilepsy is a symptom. So apparently, if I'm understanding the paper correctly, the sequences don't solve a puzzle on their own. Rather, they provide the pieces of the puzzle that are up to the doctors to solve. As opposed to stabbing in the dark, the sequencing appears to eliminate certain etiologies, and to present clues. To quote the study, "[The]... results indicate the presence of a causal variant in a difficult-to-sequence region and suggest that such variants that remain enigmatic after the application of current whole-exome sequencing technology could be uncovered by unbiased application of long-read wholegenome sequencing." I'm only a layman with just a personal interest in genetics, so I cannot say this for certain... but maybe genetic sequencing could have helped my doctors rule out genetic causes of the extrapyramidal myoclonus. In other words, genome sequencing not only can identify rare diseases directly, but it can also rule them out to some extent--or at the very least suggest that the diagnosticians look elsewhere for their answers.
