Living with Issacs’ Syndrome, a Rocky Story

A walk in the evening had left senior investment banking executive Tim Johnson in immense discomfort.

The 38-year-old based in Mumbai described a stabbing pain that had developed locally in the lumbar region and had extended to his right leg, which began cramping continuously. The next morning, the pain persisted and was accompanied with stiffness that made movements difficult. Johnson decided to consult an orthopedic specialist. It was February of 2016.

After being put on drugs with little to no improvement, Johnson consulted a gastroenterologist. He was then referred to a neurologist, and it was at this stage that Johnson received his first diagnosis of polymyositis, an inflammatory muscle disease.

Johnson’s month-long stay in the hospital involved running test after test to find a definitive diagnosis and careful deliberation of treatment. He was barely able to walk and dependent on painkillers taken three times a day. A month in the hospital left Johnson with no other choice but to resign from his investment banking work, which could not be left unattended to for so long.

By March 2016, Johnson’s team of medical experts had completed a thorough motor examination that had revealed average muscle status with wasting, stiffness in the upper limbs, excess weakness with spontaneous gross fasciculations in both arms and in some areas of the face. A nerve conduction study and EMG confirmed a final diagnosis—Isaacs’ Syndrome.

Also known as neuromyotonia, Isaacs’ Syndrome is a rare, muscle function disease currently affecting an estimated 100 to 200 people worldwide.

“It being a rare disease, the costs involved were very, very high,” said Johnson, who now works as a financial consultant. “In Indian Rupees, my bill was Rs 20 Lakhs [for hospitalization alone, about $31,000]. The rest of the costs, like travelling, were separate.”

Because the disease is so rare, Johnson has yet to meet anyone else with Isaacs’ Syndrome. But, he says he is part of a Facebook group for people suffering from it worldwide. Here, individuals can exchange ideas and share their stories.

“To be honest, I have been dealing with it alone,” said Johnson, who plans on posting in the Facebook group more often. “I am searching for a permanent solution and [trying] not to continue with symptomatic treatment only.”

Such symptoms that Johnson still deals with on a daily basis are commonly experienced among others with the disease and can occur when the peripheral nerves outside of the brain and spinal cord become easily excited, causing the muscle fibers they synapse with at the neuromuscular junction to continuously contract.1 This hyperexcitability leads to involuntary and constant muscle activity producing stiffness, cramping, and delayed relaxation, all of which can result in difficulty walking as well as fatigue.3

In a subset of cases, other symptoms may include excessive sweating, insomnia, seizures, constipation, and personality change, which may point to Morvan syndrome.3

The specific etiology of Johnson’s Issacs’ Syndrome remains unknown, but in many cases, it is either acquired or inherited genetically. In the case of acquired neuromyotonia, there is evidence suggesting the role of certain antibodies perturbing the normal functioning of voltage-gated potassium channels.2 These antibodies have been detected in 30-50% of patients.7 Neuromyotonia can also be triggered by an altered immune response to a neoplasm, or tumor, and is paraneoplastic in up to 25% of patients—often signaling potential thymus or lung cancer.7

While some cases of Isaacs’ Syndrome are acquired and may predate cancer, Isaacs’ Syndrome can be inherited as well. In 76% of patients with autosomal recessive axonal neuropathy with associated neuromyotonia (ARAN-NM), mutations in the histidine triad nucleotide-binding protein 1 (HINT1) gene on chromosome 5q31.1 were identified.4

“As far as I can recollect, there were no genetic tests performed,” Johnson wrote in an email. “PET scan was performed, and it showed no traces of cancer. [My] clinical manifestation of Isaacs’ Syndrome was typical.”

Today, Johnson is still managing his symptoms, which continue throughout the day and even during sleep. However, with a balance of medication, meditation, yoga, and walking, his symptoms have reduced in intensity. Aside from closely monitoring any changes due to medication or food, Johnson says he tries not to think about his disease too much.

Instead, he strives to keep a positive outlook on life by watching inspirational movies “again and again and again,” including the Rocky series.

“I have this quote: ‘Going in one more round when you don’t think you can – that’s what makes all the difference in your life’ by Rocky Balboa in my room,” Johnson said. “I see it first thing early morning and the day is history.”

Johnson says he views his disease both as an opportunity and responsibility to connect with more people and organizations, create awareness, and to learn more about himself.

“I wish and urge people to create the power of awareness and be a part of any social expedition to help others,” Johnson said. “Because of the position that I’ve been put in, I think it’s important to use my voice and people’s support to do as much as I can.”

The patient's name has been changed to maintain confidentiality

Sources

1. UpToDate -Paraneoplastic syndromes affecting peripheral nerve and muscle, Josep Dalmau, MD, PhD and Myrna R Rosenfeld, MD, PhD
2. Newsom-Davis J, Mills KR. Immunological associations of acquired neuromyotonia (Isaacs' syndrome). Report of five cases and literature review. Brain 1993; 116 ( Pt 2):453.
3. (https://rarediseases.org/rare-diseases/acquired-neuromyotonia/)
4. Ahmed A, Simmons Z. Isaacs syndrome: A review. Muscle Nerve 2015; 52:5.
5. Tim’s pdf document
6. http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=84142
7. Skeie, G. O., Apostolski, S., Evoli, A., Gilhus, N. E., Illa, I., Harms, L., Hilton-Jones, D., Melms, A., Verschuuren, J. and Horge, H. W. (2010), Guidelines for treatment of autoimmune neuromuscular transmission disorders. European Journal of Neurology, 17: 893–902. doi:10.1111/j.1468-1331.2010.03019.x

Tenth Annual Rare Disease Day

The last day of February is a day to create awareness and let patients and affected with rare diseases be heard. This year, February 28th marks the tenth year of Rare Disease Day.

Rare Genomics (RG) participated last year, and we will again this year be a part of a day where rare diseases get the attention they deserve. This day patients worldwide stand together and make their voices heard, and RG wants to be a part of this.

What is Rare Disease Day?
Rare Disease Day seeks to raise awareness amongst both the general public and decision-makers about rare diseases and how living with these impacts patients’ lives.

Many different organizations participate in Rare Disease Day events. Rare Disease Day started in 2008 as a European phenomenon - but today it has expanded into be a worldwide phenomenon. Hundreds of patient organizations work to raise awareness for the rare disease community in their countries all year around, but on the last day of February they get extensive public and political attention.

The last day of February was chosen as Rare Disease Day since February 29th is the rarest day and only occurs every fourth year.

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The official poster for Rare Disease Day 2017

Join us for Rare Disease Day
Rare Disease Day is an opportunity for RG to draw attention and awareness to rare diseases. The awareness is important in order to hopefully diagnose and cure many more patients with rare diseases in the future.

Please join us and participate in Rare Disease Day! Your donation to RG will help patients living with a rare disease. By donating to RG and being part of the tenth Rare Disease Day you contribute to a brighter future for the patients - a future without rare diseases.

Read more about Rare Disease Day and RG's participation here and donate by clicking the button below. Thank you!

Leading the Way: Marching Onward

At the Rare Genomics Institute, we understand that enacting change cannot happen unilaterally and that solving medical mysteries does not come without teamwork. We stand proudly at the forefront of the utilization of genomic sequencing for the purpose of identifying, treating and hopefully curing rare diseases. At the same time, we realize there are many other people outside of our organization who are just as fundamental to the fight against rare diseases as we are. The team at RG is inspired by those who dedicate their lives to helping others affected by rare disease. Here is one of their stories:

Research is the backbone of scientific discovery. Researchers do not often hone their craft in the spotlight: theirs is a task best suited at the lab bench, away from the public eye. It was, therefore, striking to come across a geneticist who works with the public on a daily basis as a pediatrician in my proverbial backyard at Columbia University. In December of 2016, I sat down with Dr. Wendy Chung to discuss her unique practice.

Dr. Chung holds both a PhD in genetics from Rockefeller University and an MD from Cornell University. The confluence of those pieces of education is not coincidental; “The year that I started my MD/PhD program was the year the Human Genome Project officially started. It became very clear to me that there was going to be a very unique opportunity in terms of being able to harness [that] power.”

Her interest in genetics in tow, Dr. Chung tailored her research and subsequent medical practice toward those who need genetic research most: children with rare diseases.

“A lot of individuals with rare disorders don't live to grow up,” Dr. Chung continued, “[However], it’s just been miraculous to me to be able to see how much things have evolved and changed in a very positive way: What I see now is that getting a diagnosis is much easier than it used to be. Now our energy needs to be focused on developing treatments. What drives me now is to figure out how we can get beyond the diagnosis and get to [those] treatments.”

Setting a Course:

The route that Dr. Chung’s lab takes toward diagnosis and treatment is somewhat irregular. Gene editing has been mentioned on the Rare Genomics Institute’s website before.

However, Dr. Chung edits the genes of model organisms (mostly mice) in order to test the reactions of those organisms to treatments before utilizing suggested treatments on humans. Dr. Chung’s practice is unique in that she and her team participate on both the research and practical implementation sides of the fence. She is actively both testing treatments and treating patients.

Dr. Chung stated, “We do everything we can in terms of clinical care and then we continue to march onward. If we don't find anything we can do clinically we cross over the fence into research mode and do everything we can on the research side. We can return information from the research study to [patients] and hopefully get them to a diagnosis faster and more effectively.”

Dr. Chung continued, “Because Columbia is a research institute, when we identify new conditions, we do our very best to help families connect to each other and to share information amongst clinicians. [We then] make that information freely available and accessible so that we can all learn together and try to understand mechanisms for why these conditions exist.” Dr. Chung detailed some of the limitations of more orthodox research methods, “If you're talking about cells in vitro, it’s a fine model for very basic molecules in terms of how they interact in a cell. But even if you make an organoid in terms of neurons in a dish, you can’t get that to function like a brain does. Maybe if you're lucky you'll get something that looks like a seizure from an electrical point of view, but often times you can’t get anything that approaches the right behavioral difference.”

Researchers at Columbia come to similar crossroads in Dr. Chung’s lab. “When it comes to mice or any other model organism,” stated Dr. Chung, “the mice may look basically fine, but the people, who have this same condition, they are clearly not fine.”

The two halves of Dr. Chung’s practice are united due to this complication. Though rodents inflicted with the same rare conditions as human patients may appear to function normally, Dr. Chung notes that mice do not read or write; they are not responsible for higher-order thinking challenges like those of a human. Therefore, sometimes, modeling is insufficient in both diagnosis and in research for treatment techniques for patients.

Next Steps:

The goal of Dr. Chung’s practice is, of course, not simply diagnosis but treatment. There are limitations to this goal, however. Research timelines often stymie a patient’s journey from diagnosis to treatment. Dr. Chung elaborates, “Treatment isn't something that comes a week after you get the diagnosis. It often takes several years to do that, but we're working with families to take that next step.”

Time is not the only limiting factor in the treatment of a patient living with a rare disease. Costs can be overwhelming for families. Accessibility is extremely important to the rare disease patient community and Dr. Chung’s team certainly recognizes the fact. Dr. Chung notes, “We take all types of insurance, whether it’s Medicaid or private insurance. We try to have enough capacity to try to deal with all of the different types of patients that would come in, whether they're kids or adults.”

“On the other hand,” Dr. Chung continued, “we also try to be realistic. If there are some individuals where, if we don’t think that there's a high enough probability that we're going to find something or help them even if we don't find an answer, we don't have them come halfway around the country.”

Working Together:

Dr. Chung’s patient population is wide-ranging in the geographic sense, and admission therein requires that only 3-5 patients are seen each week. Typical patients of the DISCOVER (Diagnosis Initiative: Seeking Care and Opportunities with Vision for Exploration and Research) Program “tend to be many of the same types of folks that you guys are working with at the Rare Genomics Institute” states Dr. Chung, “[these] kids may have neuro-developmental disorders or congenital anomalies or very rare or very early onset presentations of conditions that increase the probability that [their conditions may be] something hereditary.”

Many of Dr. Chung’s patients are designated “N-of-1” or the very first patients to experience certain conditions. Dr. Chung clarified, “Although it’s not always the case, it’s not unusual for us to be an N-of-1 situation for a while. [These situations] don’t stay N-of-1 for very long, but they often start out that way.”

The uniqueness of her patient’s conditions often leads to frustrations in treatment. Dr. Chung notes that in terms of ultra-rare diseases, the challenges of both time and money weigh heavily on the patient population, “ultra-rare diseases are individually so rare that it is hard to be able to get the resources and the talented scientists to be able to dedicate all their energies for conditions that affect one in two million people, for example.”

Emphatically reinforcing why her organization is important in the many fights against rare conditions, Dr. Chung stated, “Unless every rare disease is blessed with a family who has gazillions of dollars they don't know what to do with, you can get stuck.”

But Dr. Chung’s team needn’t help families get un-stuck alone, “This is very much a partnership. Families really have to take up the cause and push things forward, especially when it comes to the ultra-rare disorders. If they don't, it's not like a lot of people are going to run to their assistance.”

Moving forward from diagnosis is a communal effort: it is up to all of us. Whether you’ve been inspired by the work of artists or you know someone living with a rare disease yourself, the work of doctors and researchers to help patients living with rare conditions cannot be completed without your help. Please consider suppporting ongoing rare disease research efforts. Let's march onward together.

BeHEARD 2015 Winner Update: Progress on Rare Skin Disorders

Thank you for your support and interest!! Donations and information at http://bit.ly/NevusSci or http://react-community.org/projects/1 and http://naevusglobal.org CMN = congenital melanocytic nevus or naevus. These birth defects come in all sizes. This video concerns one of a few research projects in the world devoted to the largest and rarest of these, which are also the most risky from a health standpoint.

Heather Etchevers, a research scientist at the French National Institutes of Health, is a two-time winner of the BeHEARD competition for support for her research on identifying mutations that lead to giant congenital melanocytic nevus (CMN), a pigmented birth defect of the skin that requires surgery to remove.

In 2013, Heather was selected to receive a supply of JumpStart TAQ ReadyMix, a PCR reagent, from Sigma Life Sciences, which led to her lab finding the mutation responsible for CMN in eight patients. Heather was also able to use leftover reagent supplies for ongoing research to identify the genetic cause behind a second rare disease, cutaneous arteriovenous malformations. Her lab was able to eliminate one of four likely genes as a potential cause, a result that was written up for journal publication. During 2015, Heather was awarded $10,000 worth of existing mouse models from The Jackson Laboratory’s live repository, from which she selected six defined lines.

Heather and her team, “…are looking forward to using a so-called reporter mouse strain to monitor the activation of a particular signaling pathway in individual cells. With the animal model and cellular tools we are developing at the moment, [we will] develop innovative approaches to curing the worst effects of CMN syndrome (cancer, neurological deterioration) and managing the ones with psychosocial impact, such as a strikingly different appearance, relentless itchiness or otherwise less than fully functional skin.”

"It's always a tremendous challenge to attract research funding for rare diseases - even more so when we are carrying out fundamental studies in mechanisms and causes", says Heather. "RGI BeHEARD did just that - the fact that an award was attached made our research more visible and attractive for other funders."

Leading the Way: Positive Exposure (Part Two)

At the Rare Genomics Institute, we understand that enacting change cannot happen unilaterally and that solving medical mysteries does not come without teamwork. We stand proudly at the forefront of the utilization of genomic sequencing for the purpose of identifying, treating and hopefully curing rare diseases. At the same time, we realize there are many other people outside of our organization who are just as fundamental to the fight against rare diseases as we are. The team at RG is inspired by those who dedicate their lives to helping others affected by rare disease. Here is one of their stories:

Last time we began to showcase a remarkable individual whose chosen path in life is to convince the world that all people are beautiful. Rick Guidotti creates positive imagery where others choose to ignore it: his photographs allow the viewer to realize that everyone, no matter their disability or condition, is beautiful.

Beautiful Light:

This does not come without its challenges. Before photographing those with Fragile X Syndrome (a genetic marker for Autism), Rick did not know that those with the disease prefer not to look into other people’s eyes. When attending an event with the hopes of photographing some children with Fragile X, Rick was surprised when many of the children ran away from him screaming.

Looking into a camera was apparently a scary experience for these children. In an effort to remedy the situation, Rick began photographing a little girl’s doll and showing her the pictures. Giggling, she brought Rick all of her dolls to photograph. After running out of dolls, the girl showed Rick her friends at the event, and then her family. Eventually, Rick had photographed everyone in the room.

Rick’s technique in photographing his subjects (or as he refers to them, “Ambassadors”) should be noted:

(I) just turn the light on these amazing people that normally don't have a light shined on them and they're usually beaming. So many times it’s not just the person that’s beaming on the set, it’s their families that are off set that are beaming even brighter: their kids are finally being seen the way that they should be…People have so much to offer, no matter what their capacity happens to be, the joy is in there. That's what we need to see. There isn't anybody that should never be seen in that beautiful light. We should all be seen in that light. That's what Positive Exposure is about: to make sure that everybody, everybody has that opportunity.

Faces Redefining Medical Education:

Medical textbooks and training materials are in dire need of more humanized photos of people living with disease. Most imagery found in those materials is stark: it is designed to show the (often literally) naked and harsh reality of physical deformity. It ignores that those living with diseases are people, rather than objects. In designing photographs to show simply how a disease presents itself, the makers of medical texts often ignore the human element in their pictures.

Through Positive Exposure’s FRAME (Faces Redefining Medical Education) program, Rick is working with the medical community to re-craft ideas of what an appropriate image can be in a medical model.

Rick began his work on the FRAME project highlighting Marfan’s Syndrome, “I thought, as an artist, how can I present Marfan's Syndrome (with) all the information you need as a healthcare provider in training to identify Marfan's, but let’s add the most important, key ingredient which is missing in all these photographs: humanity.”

The reason for the FRAME project is simple, “Nobody, and this is across the board; nobody wants to be seen as a disease or diagnosis. We always want to be seen as a person, first and foremost. (We) also have an opportunity to see all of these great Ambassadors the way someone that loves them sees them: through the eyes of their mom or dad, through the eyes of their partners or their children or their siblings or their best friends.”

The FRAME project doesn’t end at still photographs, however. FRAME’s foundation is a series of short videos (around 10 minutes in length) that highlight the hallmarks of a disease or condition. The twist that makes these instructional videos more impactful than most: they’re told from the perspective of either someone living with (or a loved one of someone living with) a particular disease or condition.

The impact of these much more personal experiences cannot be overstated, “senior physicians have never even heard of some of these conditions before. But med students can get seven minutes where they can learn from Winnie, what these conditions are, and (they’re) going to remember it…They're going to be better healthcare providers because they saw these kids not in the clinical environment. They met these kids being kids. They met these kids not in crisis.”

Pearls Project:

Positive Exposure has taken the sentiment of the FRAME program one step further with a project simply titled, “Pearls.” It is clear that not only the medical community, but rather society at large, could benefit from a fuller understanding of each of its members. In collaboration with the Museum of Tolerance, Positive Exposure has facilitated an in-person/online hybrid educational opportunity for children and young adults so that people may begin to understand the differences among themselves.

In the program, Positive Exposure’s Ambassadors share their unique perspectives in life with others who may have questions. These Ambassadors speak about their differences, but they also facilitate more casual conversation: all in an effort to bring awareness to the community at large that our differences in a way make all of us the same.

Pearls has been particularly well-received, according to Rick, “People are just embracing (it) because (Ambassadors) are giving people an opportunity to not look away… (The) Pearls project and all of our other programs are creating opportunities to steady the gaze of the public long enough so they can see beauty in difference and then, of course, to see around that (difference).”

Moving Forward:

From April 5th through April 12th, the Art Director's Club in New York City hosted a Positive Exposure's Spring Gala. That event serves as a model for the organization's future publically. Rick is determined to feature both the FRAME and Pearls projects in future exhibitions, with an eventual eye at integrating each program into American educational programs.

It is important to not lose sight of the reason for the existence of Positive Exposure: the celebration of life and beauty, in all of its forms.

As I personally struggled to define beauty, Rick stated elegantly, “We all have our own ideas of what beauty is. In most of us though, unfortunately, it’s already been defined by somebody else's standard…Beauty is personal. Beauty is something we all should be empowered to see, and we should all be allowed the freedom to embrace our own ideas of what's beautiful.”

Hopefully through Positive Exposure, we can change how we see beauty: just imagine how much we could change.

Leading the Way: Positive Exposure

At the Rare Genomics Institute, we understand that enacting change cannot happen unilaterally and that solving medical mysteries does not come without teamwork. We stand proudly at the forefront of the utilization of genomic sequencing for the purpose of identifying, treating and hopefully curing rare diseases. At the same time, we realize there are many other people outside of our organization who are just as fundamental to the fight against rare diseases as we are. The team at RG is inspired by those who dedicate their lives to helping others affected by rare disease. Here is one of their stories:

Change how you see; See how you change:

Too often society focuses on diseases rather than the people who have them. Rick Guidotti's mission is to change that. For years, as a fashion photographer for publications like Elle, Harpers Bazaar and GQ, Rick was commissioned to photograph people who fit societal standards of beauty.

Now, as founder and CEO of the non-profit Positive Exposure, Mr. Guidotti aims to alter society’s perception of beauty by photographing those with diseases in the same way that he used to photograph supermodels.

On a cold January afternoon Rick invited me to his non-profit's studio office in New York City. Upon entering the space, it is impossible to look away from the large, vibrant, glossy photos on the walls. Rick's depictions draw you in and force you to live in the moment of each photo. The only thing tearing me away from getting lost in the images was Rick's enthusiasm about them.

Positive Exposure has been featured on NBCNews, in a documentary titled On Beauty (Kartemquin Films) and most recently as part of an exhibit at the Museum of Tolerance in Los Angeles, CA. Rick has spoken at medical schools and has given a TEDtalk as part of his passion project, and it is apparent in speaking with him that Rick has not lost sight of the importance of his work.

Describing the encounter which led him in this unique direction, Rick is candid, “I see beauty everywhere as an artist. Walking down Park Avenue, after a casting for a magazine spread that I was shooting, I saw a kid waiting for a bus with albinism. She didn't have pigmentation in her hair, her skin or her eyes. I was so excited because there was this beautiful kid, yet (she had) never, ever been included in (the) beauty standard.”

A lack of positive imagery on the subject of people with albinism drew Rick further into his work, “I found images of kids up against a wall in doctor’s offices, naked usually, with black bars across their eyes…It was so mind-blowing that this beautiful kid never inspired anything but this negativity. I couldn't find one positive image.”

So rather than find positive images, Rick was moved to create them. Through a partnership with the National Organization for Albinism and Hypopigmentation (NOAH), Rick’s first photos for Positive Exposure were snapped. His work with NOAH ultimately led to a photographic essay which would later be featured in a Life article titled, Redefining Beauty.

His first encounter in a studio with an albino model solidified Rick’s inspiration, “It was really apparent that this kid had zero self-esteem as a direct result of the bullying, the teasing and the abuse she experienced every day in school. She was breathtakingly beautiful, yet she didn't see it. She needed to change the way she saw herself.”

It was in that moment when Rick crafted the motto of Positive Exposure, “Change how you see; see how you change.” This message has now been cultivated through images of people with a wide variety of diseases, not just albinism. Rick has held his lens in front of people with Marfan’s Syndrome, people with a Chromosome 18 Anomaly, those suffering from Potocki Lupski Syndrome, and many, many others.

He photographs mostly children and young adults who suffer from rare diseases, but Rick also photographs those children’s families and friends. Positive Exposure is as much about capturing the joy and happiness of little moments in people’s lives as it is about raising awareness of the many differences among us.

In our next post, we will follow up with Rick Guidotti about the specific programs his organization has implemented. In the interim, please note that the Art Director's Club in New York City will host Positive Exposure's Spring Gala from April 5th through the 12th. The event will include interactive exhibits with a full complement of Rick's photographs as well as community talks. The movie On Beauty will be screened and a book containing much of Rick’s work will be debuted during the exhibition.

Check out Part Two of our conversation with Rick here.

The Impact Of Rare Disease Research On The Development Of New Medicines

Karla Lant of Rare Genomics Institute recently contributed to Clinical Leader with the article The Impact Of Rare Disease Research On The Development Of New Medicines.

"When we consider rare disease research and apply a cost-benefit analysis, it becomes clear that the benefits of this kind of research far outweigh the costs. Unfortunately, though, too often this kind of assessment stops short; only the immediate benefits of the research are considered. Discovery of possible cures, treatments, or preventative tools for the diseases in question are generally thought to be the only benefits..."

Read the full article >