Background on my genetic mutation causing ALS – C9ORF72 

I am doing something different in this blog. In two weeks I will be blogging about the ALS/MND International Symposium in Boston for which I was a patient fellow but could not attend due to a family emergency. A wonderful woman named Jennifer Chase, who has the same gene mutation as me, contacted me and offered to send photos and summaries from the conference. She had the same focus on this gene mutation as me so that is the research she mainly reported on. I thought it would be good give you the background on this genetic mutation before reading the conference summary. Next week I promise the end of the Hawai’i trip and our recovery and prep for Jonika and 18 month old Ollie visiting as well as their arrival. 

Here is a great summary from the jounal Nature, from their Nature Outlook: Amyotrophic Lateral Sclerosis 

Genetics: The hexanucleotide hex
by Elie Dolgin

For years, researchers missed the most common genetic cause of ALS. Now they’re on an accelerated track to treat it.

Mark Price’s family had a long history of neurological disease. His sister and uncle had died from amyotrophic lateral sclerosis (ALS), and his mother and aunt were living with dementia. But it was not until Price himself started to slur his words in 2010, shortly after his daughter Sharon’s wedding, that it dawned on him that there might be a genetic basis to his family’s tragic medical past.

Within a year, Price was diagnosed with ALS, and Sharon wondered if she — or her future children — would be next. “I stopped everything and said, ‘I can’t have a kid until we figure this all out,’” recalls Sharon, then aged 26. At first, Price’s doctors couldn’t pinpoint any defects in the ALS-associated genes that were known at the time. Then came reports in September 2011 that two teams of scientists had found a new gene linked to ALS, one that could explain up to 40% of familial cases of the disease and 10% of what are known as sporadic cases. What’s more, this gene accounted for an estimated 30% of hereditary cases of a condition known as frontotemporal dementia (FTD), providing a long-sought genetic rationale for why that neurodegenerative disorder often struck members of families affected by the motor neuron disease ALS — families such as Price’s.

Mark Price, here in a family snapshot with his daughters in 1988, was diagnosed with ALS in 2011 and found to carry a faulty C9ORF72 gene.

The genetic culprit is called C9ORF72— from its location on chromosome 9 in a region known as open reading frame (ORF) 72. And it has an unusual nucleotide sequence pattern. In some people with ALS or FTD, a short stretch of DNA in a non-coding portion of C9ORF72 is repeated hundreds or even thousands of times; in healthy individuals, the same sequence — GGGGCC — is repeated fewer than two dozen times.
In early 2012, Price was tested for the C9ORF72 repeat expansion. The test came back positive, and he died a year later. And while Sharon and her two sisters grieved for their father, they also had to grapple with the fact that each of them had a 50:50 chance of carrying the genetic defect. Now, they had to decide — would they get tested?

House hunting

The story of C9ORF72 starts with the German psychiatrist Anton von Braumühl, who in 1932 first made the link between ALS and FTD. But it was not until the mid-2000s, when the genetics of large multi-generational families affected by both disorders were studied, that researchers began to zoom in on the short arm of chromosome 9 as harbouring the gene of interest. By 2010, they had narrowed the search down to a stretch of 232,000 nucleotides — tiny by genomic standards. But none of the four genes in that region contained any protein-altering mutations that could explain the disease connection.

“It’s like we knew the street, but we didn’t know the exact house,” says Ammar Al-Chalabi, a neurologist and clinical geneticist at King’s College London.

The race was on to find the gene responsible. At least five research teams from across Europe and North America dedicated themselves to solving the problem. Many thought it would be straightforward. But C9ORF72 proved to be “very sneaky”, says Ekaterina Rogaeva, a molecular geneticist at the University of Toronto in Canada. “This region is not user-friendly.”

A group led by Rosa Rademakers, a neurogeneticist at the Mayo Clinic in Jacksonville, Florida, focused on a three-generation family in which ten individuals had ALS, FTD or both. Not knowing what to search for in these patients’ genomes, “we looked for anything that might be suspicious”, Rademakers says. That included the GGGGCC-rich section of C9ORF72.

She and her colleagues set up polymerase chain reactions (PCRs) to amplify that region and saw an unusual inheritance pattern: for everyone in the family who had a neurodegenerative disease, the PCR test showed them having two identical copies of C9ORF72 when they should have had different variants.

It was a head-scratcher for Rademakers until it dawned on her that the genetic defect was larger than the upper size limit that the PCR could read. She and her collaborators turned to a more sensitive technique called repeat-primed PCR and observed a large repeat expansion — but only in affected family members. None of their unaffected kin had it. Nor did some 1,000 healthy controls.

The researchers tested another 696 people with ALS or FTD to make sure that this repeat was not unique to the family they had studied. Sure enough, they found the C9ORF72 mutation in another 59 unrelated individuals, including 22 who had no known family history of neurodegenerative disease. Further experiments showed that the GGGGCC stretch repeated itself at least 700 times.

“Wow,” Rademakers remembers thinking. “This is something that’s going to have consequences.” At the same time, an international consortium led by Bryan Traynor, a neurologist and geneticist at the US National Institute on Aging in Bethesda, Maryland, was making the same discovery. Traynor was clued in to the repeat expansion by the technical shortcomings of a different DNA analysis method — next-generation sequencing. “It was an amazing moment sitting in front of that computer and knowing what was truly going on there,” he says.

The two teams published their results back-to-back in September 2011 in Neuron, beating other groups that were still on the hunt for it. “We were scooped,” says Al-Chalabi. “But in a sense, we were pleased to be scooped.”

In vitro fertilization has enabled Price’s daughters Sharon Stone (left) and Jodie Price to avoid passing on the faulty gene to their children. Image: Sarah Keayes/The Photo Pitch

Exciting times

The discovery had an immediate impact. The frequency of the C9ORF72 defect in patients “made everyone who’s seriously interested in ALS feel like they should work on it”, says Pamela Shaw, a neurologist at the University of Sheffield, UK.

Brian Dickie, director of research development at the Motor Neurone Disease Association in Northampton, UK, recalls flying from London to a meeting in the United States that September. It was five days after Rademakers’ and Traynor’s papers were published. Several ALS researchers and clinicians were on board and someone had printed copies of the manuscripts. “They were being passed around the aircraft as we were flying over,” Dickie says. “It was clearly an exciting time.”

Several drugmakers jumped on the finding. “It was difficult to ignore something like the C9ORF72 discovery,” says Brian Zambrowicz, head of functional genomics at Regeneron Pharmaceuticals, a company in Tarrytown, New York, that was founded to tackle neurodegenerative diseases, but broadened its strategy 20 years ago after its first drug candidate failed to help people with ALS. According to Zambrowicz, the discovery of C9ORF72 prompted the company to focus again on ALS therapies, starting with the creation of a C9ORF72 mouse model.

Ionis Pharmaceuticals, which specializes in antisense RNA-based therapies that can switch off disease-causing genes, also moved rapidly. “We put a plan together the day the papers came out,” recalls Frank Bennett, senior vice-president of research at Ionis, based in Carlsbad, California. Within two years, Bennett and his academic collaborators had demonstrated that an antisense drug could reduce aberrant C9ORF72 mRNA levels in cell cultures. They had proof-of-concept data in mouse models a little more than two years later. A lead drug candidate from Ionis is now undergoing preclinical toxicology studies, and human trials could begin early next year.

That speed, says Lucie Bruijn, chief scientist at the ALS Association in Washington DC, was enabled in part by the influx of investigators driven to deduce the mechanism by which the C9ORF72 defect causes disease. The repeat expansion recalled those found in other neurodegenerative disorders, including Huntington’s disease, myotonic dystrophy and spinocerebellar ataxia. In addition, it overlapped genetically with FTD. Researchers who study these brain diseases had historically worked in isolation. After the C9ORF72 discovery, they came together with a common purpose.

“We suddenly had a large number of clinicians and scientists interested in ALS,” Bruijn says. “That gave the field an enormous boost.” The first idea about why the GGGGCC mutations might cause ALS or FTD had less to do with the repeat expansion and more to do with the normal C9ORF72 protein. Rademakers noticed that levels of the normal protein were reduced in people with the gene defect. Although the protein’s role is still poorly understood, it is thought to be involved in the transport of molecules within cells. Rademakers’ observation led to the suggestion that lower levels of normal C9ORF72 could be driving pathological brain responses.

Initial studies seemed to refute this hypothesis. Mice with little or no expression of the C9ORF72 protein in their neurons displayed no behaviours indicative of a neurodegenerative disease, and nor did their brains have the molecular hallmarks of ALS or FTD. More recently, however, several teams have noticed immune defects in mice that lack C9ORF72 in all tissues. Together, these findings indicate that the lower levels of working C9ORF72 do not themselves cause neuron degradation, although the altered immune responses could add to the severity or progression of the disease. “It may contribute,” says neuroscientist Jeroen Pasterkamp at the University Medical Center Utrecht in the Netherlands, “but in conjunction with other mechanisms.”

No gain, no pain

The most obvious alternative mechanism is RNA toxicity. Other diseases caused by non-coding repeat expansions are explained by aggregations of aberrant RNA in the nucleus that bind and sequester housekeeping proteins that are otherwise needed for proper cell function. Pursuing this hypothesis, molecular neuroscientist Adrian Isaacs and his colleagues at University College London created transgenic fruit flies to test whether these aggregates caused disease. They were in for a surprise.

Flies with more than 100 GGGGCC repeats did indeed show signs of C9ORF72-mediated neurodegeneration — but only when the repeat-containing RNA could be translated into a protein, and not when the RNA was interspersed with translation stop signals. RNA aggregates, in other words, were not enough to cause disease. Rogue proteins seemed to be the real drivers. “I was convinced the flies would tell us it was an RNA toxicity,” Isaacs says, “but when we saw the data it was clear that that was not the case.”

The proteins that emanate from the GGGGCC expansion are created through an unusual process that does not require a start signal and can occur even with repeat sequences located in non-coding gene regions. Laura Ranum, a neurogeneticist at the University of Florida College of Medicine in Gainesville, first described this phenomenon in 2010, in tissues from people with spinocerebellar ataxia and myotonic dystrophy, and in mouse models of these diseases.

According to Ranum, the research community initially largely ignored her findings. Many doubted that the mechanism was real. Then came the RNA-binding Proteins in Neurological Disease symposium in November 2011 in Arlington, Virginia, where Rademakers and Traynor discussed C9ORF72 and Ranum spoke about the unusual form of protein translation. Scientists quickly connected the dots.

Dieter Edbauer recalls sitting in the audience, listening to Ranum’s talk, and pulling out his laptop to see what kinds of protein the C9ORF72 expansion might make. Because the repeat is six nucleotides long — and protein synthesis relies on a triplet code — Edbauer realized that C9ORF72 might yield a handful of different proteins, each containing two amino acids repeated over and over again. He typed out each of these potential dipeptide repeat proteins. “I looked left and right to see if somebody saw what I did,” recalls Edbauer, a molecular neuroscientist at the German Center for Neurodegenerative Diseases in Munich. “I thought that everybody must have had the same idea, but apparently not.”

Fifteen months later, in February 2013, Edbauer and colleagues reported that these proteins accumulate throughout the brains of C9ORF72-affected people. Within days, Rademakers and her Mayo Clinic colleagues, led by molecular neuroscientist Leonard Petrucelli, published similar findings, as did Ranum herself before the year was out.

Since then, evidence has mounted that at least some of these repeating proteins are “uniformly wicked toxic”, says Paul Taylor, a molecular geneticist at the St Jude Children’s Research Hospital in Memphis, Tennessee. These proteins seem to cause neurodegeneration by snarling up the trafficking of molecular cargo between the nucleus and cytoplasm in brain cells. “The core defect in C9ORF72 is really that nuclear transport,” says Jeffrey Rothstein, a neurologist at the Johns Hopkins University School of Medicine in Baltimore, Maryland.

Call to account

Some researchers are now willing to pin the blame for C9ORF72-mediated disease entirely on these problematic proteins. “I won’t mince words here: the toxic poly-dipeptides do not contribute to the disease, they account for the disease,” says Steven McKnight, a biochemist at the University of Texas Southwestern Medical Center in Dallas. McKnight describes RNA aggregates and decreased normal C9ORF72 protein levels as “sideshows”.

“The evidence is pretty overwhelming that it’s the protein that’s toxic in these simple model systems.”

But most researchers are more equivocal. “The evidence is pretty overwhelming that it’s the protein that’s toxic in these simple model systems,” says Aaron Gitler, a molecular neuroscientist at Stanford University School of Medicine in California. However, he adds, “in the context of human disease it could be some combination of factors, and I have to keep an open mind.”

The debate over disease mechanism is not purely academic: it guides drug development. Some companies, including Neurimmune of Zurich, Switzerland, and Voyager Therapeutics of Cambridge, Massachusetts, focus just on blocking the repetitive proteins or preventing their formation, whereas others, such as Karyopharm Therapeutics of Newton, Massachusetts, hope to mitigate defects in nuclear transport without targeting any C9ORF72 gene products directly.

But some therapeutic strategies, such as antisense, do not depend on what the mechanism actually is. Because antisense drugs can shut off the production of both RNA and proteins, it does not matter which one is the causative agent in brain cells, says Paul Bolno, chief executive of Wave Life Sciences in Cambridge, Massachusetts, which is on track to start testing a C9ORF72-targeted antisense therapy in patients next year. And because you can track levels of the repeat proteins in the spinal fluid, it is straightforward to assess whether the drug is working. “You do have a measurable biomarker,” Bolno says.

Given how far researchers and drug companies have come in such a short time, it’s entirely possible that an effective therapy for C9ORF72-mediated disease will be available if more of Mark Price’s relatives start to develop symptoms of neurodegeneration. Haley, his youngest daughter, finds that prospect encouraging. “Hats off to the scientific community,” she says. But she worries that policymakers aren’t doing enough to support preventive health measures available today, to help avoid C9ORF72-related disease in the first place.

For family-planning purposes, Haley and her sisters all opted to find out their C9ORF72 status soon after their father tested positive. “Unfortunately,” says Jodie, the oldest, “it was bad news for everybody.” Each sister has since gone through multiple rounds of in vitro fertilization with the added step of checking that the embryos were free of the C9ORF72 defect ahead of implantation. It was emotionally, physically and financially taxing on everybody, costing at least Aus$150,000 (US$120,000), they estimate. Ultimately, however, “it was a confirmation that the science worked, and we could get rid of the family curse”, says Haley.

Sharon’s son Jack recently celebrated his third birthday, Jodie is expecting a daughter in mid-November, and Haley has two frozen embryos, ready to use after her wedding on 9 December.

This article is part of Nature Outlook: Amyotrophic lateral sclerosis, an editorially independent supplement produced with the financial support of third parties. You can find the whole article here:

 https://www.nature.com/collections/dmpwblhnbt

The Best Laid Plans (again)

​The best laid schemes o’ Mice an’ Men 
Gang aft agley,

An’ lea’e us nought but grief an’ pain,

  For promis’d joy! 

From Robert Burns To a Mouse 

Source:The Poetry Foundation 

This poem was most famously used by John Steinbeck in the title of his book  Of Mice and Men. The modern version of this quote is The best laid plans of mice and men will often go awry.

Well both Robert Burns’ version and the modern version of that quote fits my Patient Fellows experience for the ALS/MND International Symposium in Boston. It was all planned as a great trip with visits with relatives and dinner with the Patient Fellows who I have gotten to know in conference calls and emails and social media, and also a water workout with the amazing ALS athlete Andrea Peet. The day before we were supposed to fly to Boston, my husband, Stan, got a high fever and ended up in the Emergency Room with severe sepsis. So obviously we had to cancel our trip. Septic shock is life threatening and we got Stan to the hospital just in time, thanks to good friends I was able to text and who came right over and took over.  They called 911 and helped me get Stan’s bipap ready to take with us.

He was in the hospital for a week and it shook me to the core that he almost died. And it was hard on our son getting ready for Junior year final exams.

Stan survived thanks to antibiotics. And “what doesn’t kill you makes you stronger” is usually true. However, it is his medications for his Sarcoidosis that are making him susceptible to infections. Long term prednisone use weakens the skin and his wounds don’t heal without intervention. Unfortunately he will now have to stop taking Humira, which was our best hope for getting him off prednisone, and that is terribly disappointing.

But back to the Patient Fellows experience. Through the ALS/MND International Symposium meeting app on my phone, another woman who has the C9orf72 gene mutation messaged me. When I told her I had to cancel she agreed to send me updates throughout the conference. She loves science and loves to write, so her updates were great and I will be able to share her insights. Also, one of the patient fellow committee members will be sending me notes on some of the sessions I wanted to attend. So I will be able to do a blog about the meeting without having been there.

For the people who contacted me with comments for researchers, I was able to forward them to one of the Patient Fellows group members. So hopefully I will be able to address your concerns.

I was disappointed to not visit Aunt Candy and Uncle Bill, nor my godmother Alice, nor my cousin Len. I was really looking forward to seeing them.

However I also got antibiotics for a sinus infection this week, and I got handicap license plates due to my shortness of breath and the progressive nature of my disease. That will be a big help with my shortness of breath and carrying my portable cough assist and suction.

It was difficult single parenting my 17-year-old while Stan was in the hospital. But wonderful friends brought food for Andy and Erika came and stayed one night and my dad ran errands for me.

I started Round three of Radicava on Friday and will finish this round in Las Vegas on Christmas Eve, where we will spend Christmas with Stan’s dad and step mom.I am still able to care for my houseplants and my jade plant is blooming! That makes me happy.

We had a happy early Christmas celebration with my dad and Anita Friday night and that also made me happy.

We are blessed with great friends and great family. Happy Holidays to all, and especially all people with ALS and their families.

Through the holidays I will plan a blog post every other Monday, so my next post will be New Years Day. Here’s to breakthroughs in ALS in 2018.

I will end with another Robert Burns poem.

Should auld acquaintance be forgot,
And never brought to mind?
Should auld acquaintance be forgot,
And auld lang syne?

For auld lang syne, my dear,
For auld lang syne,
We’ll tak a cup o’ kindness yet,
For auld lang syne.

And surely ye’ll be your pint-stowp,
And surely I’ll be mine!
And we’ll tak a cup o’ kindness yet,
For auld lang syne.

For auld lang syne, my dear,
For auld lang syne,
We’ll tak a cup o’ kindness yet,
For auld lang syne.

We twa hae run about the braes,
And pu’d the gowans fine;
But we’ve wandered mony a weary fit
Sin’ auld lang syne.

For auld lang syne, my dear,
For auld lang syne,
We’ll tak a cup o’ kindness yet,
For auld lang syne.

We twa hae paidled i’ the burn,
Frae morning sun till dine;
But seas between us braid hae roared
Sin’ auld lang syne.

For auld lang syne, my dear,
For auld lang syne,
We’ll tak a cup o’ kindness yet,
For auld lang syne.

And there’s a hand, my trusty fiere,
And gie’s a hand o’ thine!
And we’ll tak a right guid-willie waught
For auld lang syne.

For auld lang syne, my dear,
For auld lang syne,
We’ll tak a cup o’ kindness yet,
For auld lang syne.

Auld Lang Syne a Christmas & New year poem by Robert Burns
Source: https://m.carols.org.uk/auld_lang_syne_burns.htm

I’ve been out walking….I don’t do much talking these days

I’ve been out walking

I don’t do too much talking these days

from These Days by Jackson Browne

The second line of this song states the obvious: My Bulbar onset ALS has taken away my ability to speak. But the first line is approriate for the last week too, as you will see. 

On Friday last week Stan and I drove to San Francisco for my 11:30 A.M. Botox appointment at the UCSF Movement Clinic on Divisadero. Google maps sent us across the San Rafael Bridge and Golden Gate Bridge, so we avoided the ever present traffic jam in Berkeley. On the way down we were listening to KQED public radio about the planned white supremacist rally at Chrissy Field the next day. And then we heard about all the counter protests planned, so there would be lots of places to avoid on Saturday.

This time I had a higher dose of Botox in my parotid glands, top and bottom. Then for the first time, I had injections in my maxillary glands, under my jaw. The injections really sting when they go in. As I write this, it seems I can finally discontinue my Robinul, which takes water out of your saliva and other places in your body too. I have really disliked the effect on my eyes – either too dry or too teary. I hope my eyes go back to normal. I am trying to get used to this new saliva situation – a little maxillary dribble, the rest of my mouth dry, and post nasal drip that collects in the back of my mouth.  

We moved on to my 1 P.M. appointment at the ALS clinic on Parnassus. This was another appointment with no real changes. I got some suggestions such as probiotics to control the diarrhea that often comes with tube feeding. I also got a prescription for a liquid mucous reducer because mucous collects in the back of my mouth and then I can’t breathe through my mouth, which is ok as long as my nose is clear.  But my nose is not always clear. So far that new med works well with my cough assist machine and suction. I don’t want to carry those around with me but I might have to. We did get nabbed for a research blood draw, where Stan would be my control. We were happy to participate. I don’t know why I am still walking and moving with no limb involvement even after a year. It is a rare form of ALS I am told. I can only attribute it to luck but I will do my best to help find a cure while I am able to be active.

After finishing after 5 pm, as usual, we headed to cousin Julie’s in Outer Sunset near the southwest corner of Golden Gate Park.

Her house is the most beautiful in the neighborhood.

Big Junipers in front of Julie’s house.

We watched the news about the rally being cancelled. In my opinion it was all a publicity stunt.

On Saturday we had a lazy morning and then stayed in Julie’s neighborhood anyway, with a walk through the park. I had never been through that part of the park before and it was cool. Julie is a horticulturalist, so she could tell us about many of the plants and trees.

We saw bison, which was a surprise for me. Then we saw the fly casting ponds, another surprise. 

Wedding photos by the fly casting ponds.
An apparent professional woman fly caster practicing
Stan with a flower to go with his shirt that he picked up off the ground.

My allergies were bad walking through the park but I still enjoyed it immensely.

We had an early dinner at the favorite Thang Long Vietnamese Roast Crab restaurant 3 blocks away and had a leisurely walk home.

Stan carrying Roast Crab leftovers.
An intolerant sign in a store window – very San Francisco!
A bookmark Julie had. Truly profound words from Jimi.

When we got back to Julie’s she shared some photo albums with photos of Stan’s great grandparents and her grandmother (Stan’s great grandfathers sister), plus photos of Stan’s grandfather and his siblings.

Stan’s great grandmother, Katie, and great grandfather, Billy. Billy was from Scotland and moved to New Zealand for mining work and that’s where he met Katie. Stan’s grandfather was born in New Zealand.

There was also a photo pamphlet of the exhibition for which the Palace of Fine Arts and several other palaces were built. This was interesting to me because we had learned about the exhibition when we visited the Palace of Fine Arts on Segways a few weeks before.

The Palace of Fine Arts was built as a temporary structure made out of chicken wire and Paper Mache, since beautifully restored with more durable materials.

Sunday brought another lazy morning. 

Beautiful flowers from Julie’s garden in our room
Sunflowers in the bright, sometimes sunny, kitchen. We were visiting in “Fogust” as they refer to August in San Francisco, and we were in the foggy part of town.

Stan picked out all the leftover crab to use in a beautiful breakfast of crab benedict that smelled good.

In the afternoon. we walked in another part of the park I had not seen before. Since I moved to Reno in 1985, I have been to San Francisco hundreds of times, and it’s cool that there are still so many hidden pockets that I can explore for the first time.

This windmill is right across the street from where I started the San Francisco Rock n Roll Half Marathon. It was dark when we started and I did not notice the two windmills.
In the spring, this is a tulip garden

After dinner at Julie’s, we moved to a hotel closer to my Monday through Wednesday research appointments.

I participated in a number of studies at the UCSF Memory and Aging Center, all related to the C9ORF72 gene mutation I have that can cause ALS, Frontal Temporal Dementia, or both.

On Monday I was scheduled to have an MRI. When I had my brain MRI pre diagnosis, my claustrophobia caused me to bail out of the MRI as soon as they put the cage on my head. I then had a rescheduled MRI under anesthesia. When we began looking at research and clinical trials, I made a promise to get over my MRI claustrophobia if I participated in any that required MRI.

First I had to sign a lot of consent forms. Shoshana was our study coordinater, and she was wonderful to work with. While I was signing consent forms, Dr. Nick Olney came in with his own consent form. He is researching nuerofilament-light and a cervical spine imaging method called phase sensitive inversion recovery as ALS biomarkers. Dr. Catherine Lomen-Hoerth, the director of the UCSF ALS Clinic, had told him that I was coming for research and with my unusual ALS, limited to the Bulbar region, he was interested in my spine. His dad, Richard K. Olney, MD, was the former director of the UCSF ALS Clinic and a renowned ALS researcher who developed ALS himself and died in 2012. So the younger Dr. Olney is highly motivated by his dad. He was very understanding of my claustrophobia, claiming to have it himself. He suggested I try Atavan, which we could pick up at Walgreens at lunchtime. I had my brain MRI scheduled for 1 P.M. and Dr. Olney had scheduled his for 5 P.M. So, it was a great day to overcome my phobia, with two opportnities.

I had blood drawn after the consent forms and then we went off to Walgreens and lunch.

For the first MRI I requested meditative music. I closed my eyes and didn’t watch the cage being placed over my head or myself being pushed into the tube. When I did open my eyes, I could see the MRI tecnician and Stan in the mirror. I meditated using the body scan method we had learned at the Mindfulness Course we took at St. Mary’s Health and Fitness Center. The technician checked in with me between each scan, asking for a thumbs up if I was ready to go on. I only came out once to wipe out my mouth. I pushed through the rest if it with my omnipresent napkin in my mouth. Stan was asked to do his Caregiver Interview while I was being scanned. He was able to get on the microphone and say goodbye and flash our ASL “I love you”, which I was able to return.

After the MRI, I  had the first part of a neurological exam, and then it was time for MRI number 2.

With Dr. Nick Olney, no claustrophobia this time!

This MRI was a little different because the table was moved between scans and even shaken at one point. They were good about telling me how long each scan would be and made sure I was good to go. They told me I actually fell asleep toward the end. We finished after 6 P.M. and were about the last to leave the building. It shows the dedication of these researchers to help people with ALS even if it means working late. And I was successful at overcoming my claustrophobia, which I consider a victory.

We met our friend Roy at our hotel. Stan used to work with him and he is now working in San Francisco.

It was great to catch up with a good friend.

On Tuesday, first I completed the neurologic testing with Dr. Dana McDermott. Dr. Olney came in and did his own assessment.  Then I had cognitive testing; we had a family history meeting with Joanne, the genetics counselor; more cognitive testing; then a Family Conference, with about about 15 people around a big table. Dr. Adam Boxer led the meeting. Everyone introduced themselves and it was an international group. He explained that I was participating in several studies, specifically 

  • ARTFL (Advancing Research & Treatment for Frontotempemporal Lobar Degeneration) program based at UCSF.
  • Frontotemporal Dementia: Genes, Images, and Emotion

    My C9ORF72 repeat expansion genetic mutation has resulted in ALS. For many of my ancestors, it resulted in FTD. One of the things they are trying to figure out is why the there is a such a difference in gene expression even in the same family. I will not receive any information from this study, although I did find the cognitive testing to be easy. I will come back in a year for follow up.

    After the family conference we were free to leave (5 P.M.) When we got back to the hotel, I went to the pool and did my aqua fitness. It was really nice to be exercising.

    On Wednesday, we completed the research with a Lumbar Puncture or spinal tap, which sounds worse than it is. You can decide yourself after you see the photos. They put on music for me and this time it was Jackson Browne and the first song was These Days. Of course the second line stuck with me: I don’t do much talking these days, because it’s true. The first line also stuck with me because I am blessed to still be walking. So now you see one of the random ways my mind comes up with themes for this blog.

    But now, time for the lumbar puncture. They had me sit with my head on a pillow on a table.

    Dr. Dana McDermott getting ready to sample my cerebral spinal fluid.

    First she numbed my skin, then the layers below, and then stuck the needle in. I felt shooting pain in my left sciatic nerve, and when I reacted she asked if that was what is was. When I nodded she said she would move over a little. I didn’t feel anything else.

    Sampling the CSF. I requested that they sample some extra to send to Cedars Sinai, so I would not have to go back to L.A. for a second lumbar puncture. One spinal tap for two studies sounded good to me.

    After the spinal tap, Dr. McDermott asked if i would do it again and I said yes. It really was not bad at all. This is good because the antisense drug therapy that will go into safety testing soon will be administered directly to my cerebral spinal fluid. After the spinal tap, I got to rest and my awesome sweet husband fed me my breakfast.

    Then we had a language test that was made fun by Ariane, a speech pathologist from Australia. 

    She looked in my mouth with her torch, I mean flashlight. I told her that we had been to New Zealand, so we were used to the language differences, and that Stan’s grandfather was born there. She said to him, “oh you have kiwi blood, that explains a lot”. And my jokester husband teased her about escaping from the penal colony. I said that we called flashlights flashlights when we were in New Zealand. There was a Serbian intern observing and I asked her how to say flashlight in Serbian and she couldn’t remember so she Googled it. Another funny part was when Ariane sounded out words phonetically to see if I could understand that context. She tried to do P O T but with her Aussie accent I had no idea what word she was saying. She asked Stan to read it and I got it easily. She said that sound is really hard for her to say the American way. There were other laughs but to describe them would give away too much of the study.

    Then we got information about donating my brain, which we opted to look over later. Then we were done and we had lunch and drove home.

    I am passionate about helping to find a cure for this genetic mutation, as well as a cure for all types of ALS, so I am doing all that I can.

     

    A Week of Love, Connection, Connections, and Hope

    While Andy was at camp, Stan and I had a busy week of travel. But first, after Andy left on Sunday, we had a lot of visitors. Stan’s friend Marc from work stopped by to visit. Then my neighbor and friend Amanda stopped by for a visit. Thanks Amanda! We are lucky to have your family as neighbors.

    Then Stan’s uncle Pete and his wife Mariana, from Corvallis, Oregon, visited. They were in town for the 150th anniversary of the two room old Huffaker School that is now at Bartley Ranch Regional Park. Pete and his sister Sally, Stan’s stepmom, both attended that school when it was at Huffaker Lane and South Virginia. We had a nice Italian dinner at Zozo’s with them.

    We had not seen them in many years so it was great to reconnect.

    Then Monday morning Stan and I took a 6:30 AM flight to LAX (Los Angeles). We saw this great Lexus while we waiting for our Uber.

    “Sorry Dad”

    We went for my screening appointment for the C9orf72 gene mutation biomarker study being conducted by Washington University in St. Louis, Missouri. Cedars-Sinai Medical Center in L.A. is the closest location to Reno for me to participate. We arrived at 8 and my appointment was not until 11 so we were able to have breakfast before getting our checked luggage. We Ubered to Cedars-Sinai even though we would be early. We had a nice chat with our Uber driver who was from Bogata, Colombia. His brother is a professional bike racer here in the U.S., so he had just watched the Tour de France like we had. He knew a lot about the successful Colombian riders in the Tour. He also did a good job of convincing us that we should visit Cartagena, Colombia, an old colonial city with many beautiful old buildings. He said Bogata is not safe, but it would be difficult for us at such high elevation too, since Stan and I both have lung issues. I still love Spanish so it was an enticing idea.

    At Cedars-Sinai, I signed the consent papers for the study, which will look at the C9orf72 gene mutation for each ALS patient in the study to see if there are differences in the mutation that correlate with the way and the age the disease presents itself. I went through a detailed medical and family history, had my current ALS-FSR measured (a measure of disease progression by loss of functionality), I had blood drawn, and I had a neurological exam. Stan also had to fill out a questionnaire about me.

    The gene mutation occurs as a repeat of part of the genetic code. If the repetitions are above a certain number the patient would eventually develop ALS or Frontal Temporal Dementia (FTD) or both if everyone lived to be 150. For those of us that were born with this mutation, it is believed that our bodies are able to overcome the damage the mutation causes until they can’t anymore, and then the disease manifests itself.

    This study must be completed prior to clinical testing of antisense gene therapy, which could begin as early as 2018. They said that a spinal fluid test is optional. I volunteered because I want to help advance the science as quickly as possible, for my siblings, cousins, son, and niece and nephews. The spinal tap will be scheduled at a later date.

    We were done in time to check into our hotel and walk to a nice lunch. Then Stan took a nap and I went to the pool and did my aqua fitness.

    Then the next morning we had breakfast by the pool.

    The plan after breakfast was to Uber to Orange County to visit with Lynne and Augie Nieto. Augie is Chairman of the Board of ALS TDI and Lynne is on the board too. We ordered Uber at our hotel and soon got a call from a driver who said she couldn’t get there due to a street closure for tree trimming. She asked us to walk two blocks to the other side of the tree trimming.

    So we did. You can see our hotel in the picture – the big building two blocks away. Then Uber called to tell us the driver was at our hotel. Big Uber Fail! They sent another driver, who picked us up and drove us to our destination. She had all types of phone charging cords which was nice. My only complaint was either really bad shocks in the car or really bumpy highway or both, because it was difficult to knit on the hour plus ride. We arrived just after 11.

    Lynne and Augie welcomed us to their beautiful house on a cliff over the Pacific Ocean. Augie has had ALS for 12 years. He started the fitness company that made Life Cycles. His Augie’s Quest raises millions for ALS TDI each year. We talked about fundraising we could do in Reno. Augie showed us the trailer for the new documentary about him, as well as a television news segment about him working with Project Walk, a group that works with spinal injury people to help them walk again. Augie is the first ALS patient they have worked with. He was able to walk his daughter down the aisle at her wedding, with some assistance. But even months before, that wasn’t imaginable. He worked out every day very hard to get to do that.

    I told Augie that I like his song, Augie Nieto by Five for Fighting. The song ends with a quote from Augie: “It’s not the breaths you take, it’s how you breathe.” Beautiful. They liked my ALS SUCKS t-shirt. I said I like that it has a turtle on it because we are still ourselves inside our shells of ALS bodies.

    They had a meeting at noon and we overlapped a bit so we met a lot of other very nice people.

    Then we had a very nice spot to wait for our Uber ride back to LAX.

    We thought it odd that were lifeguards so high up the cliff, but it turns out they were counselors for the Junior Lifeguard Camp for kids. Parents were coming to pick up their kids.

    We arrived at LAX at about 3 PM and our Uber driver told us that we were smart to get there before 3 because traffic later is much heavier. He said that 2 out of 10 rides that he takes to LAX, the passengers miss their flight due to traffic.

    This time we were changing planes in Las Vegas. We saw this sign at LAX.

    Can someone from visitRenoTahoe.com please explain what demographic group you are targeting? It wasn’t mine, because I don’t get it.

    Our flight out of LAX was delayed due to a crew delay. We ended up landing in Vegas when our next flight was due to depart. Tight connection. We rushed to the next gate and the gate attendant said, ‘The Macdonalds?” because we were the last two they were waiting for. He said they would wait for our bags too. Nice #Southwest. Even with this delay we arried in Reno on time.

    Then we had two nights and one day at home. It was a day of recovery for me. Stan didn’t get to rest. He met a friend for breakfast, went to wound care (wounds on his legs don’t heal due to Prednisone), and had lunch with another friend. He rested in the afternoon. I went to 5:30 pm Aqua Fitness. It was a great class – we kneeled, sat, and stood on boards which is a great core workout.

    On Thursday we drove to San Francisco to meet our friends Barb and Barry from Ottawa, Canada. Barb had visited us in Reno last fall. Barb was in San Francisco for a geriatic pharmaceutical convention which ended the day before. We checked into the Bed and Breakfast and then met Barb and Barry at the cocktails and hordeurves downstairs.

    This was the first time we met Barry. We all had a great time. That night we ate at a Morroccan restaurant called Mourad that was very nice and had great food  (it looked and smelled great to me).

    The beautiful wood at the entrance.

    Then on Friday, we did a segway tour of the city. Barb said they had always made fun of the segway tourists, but secretly they wanted to try it!

    We had great training, first right outside the segway tour place and then in a parking lot.

    Stan was the first to try. That is our great Irish tour guide behind him.

    We were in a group of 8, the 4 of us and a family of four with two teenagers. We all picked it up quickly. The change of balance is all in your feet so it seemed similar to regular downhill skiing. We stopped at a museum with arcade games from a hundred years ago and newer, along with the first photo op.

    Here we are with Alcatraz in the background.

    Then we went to the municipal pier, aka the Segway raceway. Stan really enjoyed this part.

    Barb with Coit Tower in the background

    We then went to the public parking lot by St. Francis Yacht Club where good pictures of the Golden Gate Bridge could be taken. It was partially fog covered.

    The next stop was the Palace of Fine Arts. I had driven by countless times but never stopped. It was so beautiful.

    And then, because our group all caught on quickly, we got to go up to the top of Lombard Street and ride down. This was a highlight for me – both the steep climb up and the winding ride down past all the beautiful houses and flowers. We were instructed to refer this as “chocolate” because not all the groups that left with us got to do that.

    After the Segway Tour, we had an In N Out Burger lunch so Barb and Barry could experience the California icon. Then Stan and I headed back to the Bed and Breakfast to rest and Barb and Barry went to the Exploratorium.

    That night we met Jen from ALS TDI and her husband Jimmy at a Thai restuarant. We had a lot of laughs. What a fun group.

    The next morning, after a final breakfast together, we had to say goodbye. We were headed back to Reno and Barb and Barry planned to take the ferry to Sausalito and walk back over the Golden Gate Bridge. They would fly to back to Canada the next day.

    My eyes are closed, oh well. It was a nice parting breakfast discussion, including when we could possibly meet again.

    We drove back to Reno and got there just in time for Stan’s wound care appointment. Another close connection. After that we went home and saw Andy who had arrived home from camp. As if we hadn’t already done enough this week we went out to Animal Ark for their Cheetah Dash. Animal Ark is an animal refuge that takes injured or abused wild animals. A few times a year they invite people out to watch the cheetahs run. They have devised a very fast pulley system to pull the lure that the cheetahs chase. The fastest one we saw went 50 mph.

    The best thing to come home to was our son.