Loved ones visit from Hawaii and positive changes ensue

There is so much about Jonika and Ollie’s visit that was wonderful. Jonika was helpful, cooking, cleaning, instigating organization for Andy in his bathroom, his room, and in his schoolwork. She even shared her knowledge from two years of weekly therapy to improve our family dynamics. And she also visited with friends and family.

Even Ollie (18 months) likes to help – he likes to shake my food and even pour it (but I can only let him ‘pour’ empty ones), and he likes to help with laundry, and he sweeps. It was great to watch him learn. I was packing up some things to give away that had to fit in the box a specific way. He would watch me put a piece in, then try himself and hand me the next one so he could learn how it fit correctly. He also loves to bounce on beds, swing, and rock in the rocking chair.

in the rocking chair with Granny M

And it was great that he knows some American Sign Language, especially now that I am learning some too. He and I communicate in facial expressions and hand movements, just like communication is done in ASL. When we visited Hawaii when he was only 3 months old, I was still verbal with only vowel sounds and that was all he could do too.

So far, no problem communicating with this young human although his verbal skills are increasing and all I can do now is a monotone sound.

Toddlers also bring home germs. Ollie threw up Thursday morning and by Saturday Andy, Stan, and Jonika were all sick. I had to go into mom mode and clean up Andy’s bed linens so I was exposed.

Andy convelescing on the couch watching the Olympics while Stan rallies himself to entertain Ollie

And sure enough, 48 hours after exposure I got the bug. But I was ready with my extension tube on my Mic-key button and an extra large plastic cup next to me all night. When I woke up with my button hopping up and down and I got that about to throw up feeling, I opened the tube into the cup. Even laying on bed it exploded in bursts into the cup. When I got up, I started with Gatorade and when that stayed down I did my meds. For new readers, you won’t remember my norovirus when I was still working. I could not stop vomiting and it would get stuck in my esophagus, burning away, until I could cough assist it out. That was only resolved with hospitalization. It was miserable and my esophogeal muscles work even less well now.

It was a snowy day, so Ollie got to go out and experience it for the first time. He was fine, walking around in wonder, until he fell and his hands got too cold. Then he cried and cried, and I think he was saying, “Take me back to Hawaii Mom!”

I had some more Gatorade and went back to bed. I slept a couple hours, then did cough assist and suction and had some more Gatorade. I kept the extension tube connected so I can monitor what comes out while I’m awake. By noon, I was able to tolerate one box of food.

My friend Alice stopped by to bring me some slipper socks, perfect for a snowy day.

In addition to extra family and friend visits during their stay (which were wonderful), Jonika had recommendations for our interactions with Andy. She has the unique insight of a 30-something adult, who is now a mom, and who spent four years being parented by us. One thing that really hit home was that we have to be role models, including cleaning up our cluttered areas if we expect Andy to keep his things uncluttered. So I worked on my office, which had been on my to do list for a long time. It is something that I have to do before we can do taxes. But this time, I am purging big time and I ordered a new rug to help motivate me. Another thing is to help Andy with time management, but only if wants help, and that has already helped more than once.

Jonika and Ollie left to fly back to Hawaii early on Wednesday morning. All three of us will miss them greatly.

January blues, February hopes

What is it about the month of January that is depressing? So many of my friends with ALS wrote about depression last month. There was even a widely shared post about the choice of death or divorce – a man in the United States who decided to get a tracheotomy rather than dying and his wife divorced him after that because of the burden of care.

I have had my own pity party because of the post nasal drip and drooling and mucous that are still plaguing me. My neurologist at UCSF said it is not an ALS problem. She has not seen it before. I went to an ENT in Reno and a CT scan of my sinuses was clear. But now I have an expitided referral to the UCSF ENT department (we will see how they define expedited). The next step after, if needed, will be my Gastroenterologist and the earliest appointment I could get is April 4.

Let me tell you what this has evolved to – I get bad sinus headaches to the point of bad eye pressure and sometimes even ear aches. I have found that using Mucinex every 4 hours followed by cough assist and suction sometime in between can usually keep things moving. I also try to stay upright – standing or sitting to facilitate gravity assisted movement through esophagus. It takes a lot of time to manage and makes it hard to have plans away from home. But if this is my very own ALS journey (and it obviously is) I will have to readjust my expectations and figure out how to be happy with this.

It reminds me of my ALS diagnosis saga – every new antibiotic or doctors appointment brings hope that things will be better. And every failure is depressing like the lack of finding problems was during the “Please anything but ALS” phase.

But I have read beautiful memoirs by people with cancer (When Breath Becomes Air by Paul Kalanithi and The Bright Hour: A Memoir of Living and Dying by Nina Riggs). Both described their lives with cancer and it sounds in many ways worse than ALS. Although neither book dwelled on the difficult or painful parts, they were mentioned. I guess the only easy way to die is suddenly. One happy outcome from those two books is that Paul’s wife and Nina’s husband are now in love.

So I am challenging myself to find a happy outcome. I can plan on getting help soon at UCSF and at my Gastroenterologist in April. And I can fake it until I make it or until it is over. I am lucky that I am not aspirating this thin drainage. I am lucky it is not affecting my breathing, although I often can’t make through the night with my bipap because of too much mucous in my mouth. And I am lucky to be able to still use my hands and arms and legs.

Because I can still use my hands and arms, Stan and I decided to take a Community Education American Sign Language (ASL) class. It is frustrating for Stan when I do charades not very well so our communication has been difficult. Plus if we use my phone to navigate, my voice is the same as the GPS lady who says, “Take the second left”. We had the first class and it was fun with a great teacher. It was overwhelming at the beginning but with practice it became easier. Finger spelling has already helped us. Once when Stan was leaving and I had some mail to go out, he asked where it needed to dropped and I finger spelled our mailbox. That saved me from having to run to get phone or Boogie Board or paper and pen to write. Fingerspelling has also been helpful riding in the car. We were also told that practicing fingerspelling while driving or riding in a car with license plates and signs would be a great way to start. We have a lot of online homework, but it is fun. I love that it is a whole body language and I have always loved learning languages.

Other things keeping us busy are Jonika and Ollie visiting until 2/14. They are a joy to have with us.

Jonika and I took Ollie to the playground at Idlewild. One of the play structures had the American Sign Language alphabet!

A Hawaii boy riding a whale!
A Hawaii boy with a Nevada light saber!

Jonika’s best friend Lyndi came over with her same aged son Landon.

It was so nice to see Lyndi again after so many years.

We also had a nice visit with Stan’s mother, Sharon, and Jonika’s mother, Terry. We enjoyed a meal at Naan and Kabob and relaxing visits at our house.

And more Ollie cuteness:

Last Friday we left as soon as Andy got home from school, and drove to Sacramento’s Golden 1 Center for the Kings versus Warriors NBA game. We met my best friend Erika and her kids there. It was very loud so Ollie had ear protection.

Photo by Erika Gotsch Peters
Lazy eyed me with my best friend! (photo by Erika)
Andy with his buddies Maddie and David
It was exciting to see so many NBA stars playing a good game
Photo by Erika Gotsch Peters

Jonika and Ollie were ready to leave after the third quarter so Erika and I left with them and went back to Erika’s house in Eldorado Hills. It meant we missed the fourth quarter where Kevin Durant took over and brought the Warriors to victory. But it gave us more time to visit with Erika and Stan stayed and had fun with the older kids.

The next morning we had a nice breakfast and more fun with Ollie.

Photo by Erika Gotsch Peters

Then we drove to El Cerrito to pick up Andy’s viola bow which was being rehaired. We stayed in Oakland on the estuary. Saturday night we drove across the Bay Bridge and across San Francisco to cousin Julie’s. Julie had not seen Andy since he was Ollie’s age and she hadn’t seen Jonika since she was a teenage highland dancer. Julie’s grandmother was Stan’s great grandfather’s little sister and they were from Scotland. We had a wonderful visit.

Julie was very close to Stan’s grandparents Mac and Olive, and she loved, as we all do, that Oliver was named after Olive.

On Sunday morning we met Jonika’s friend Rob for brunch in Oakland. Rob is Jonika’s mother’s best friend’s son so they have been friends since childhood.

Then we drove home, listening to the first quarter of the Super Bowl on the way.

And so began February, with good distractions from my illness, and hopes that things will soon get better with my sinus problem.

Exciting New Research

(all photos by Jennifer Chase)

I was chosen as a patient fellow for the ALS/MND International Symposium in Boston in early December. I was looking forward to learning a lot and meeting researchers and the other patient fellows.

The day before we were going to fly across the country to Boston, my husband, Stan, was hospitalized with life threatening septic shock. This forced me to cancel my trip to the conference.

But through social media and the ALS/MND International Symposium phone app, I got a message from a woman named Jennifer Chase, who has the C9ORF72 gene mutation like me. Jennifer lost her mom (who had FTD then ALS) and sister to ALS and her sister was one one of the first commercially tested patients confirmed to have the C9ORF72 gene. Jennifer is a brave sister in that she decided to get tested herself. She does have the gene mutation and has been learning all she could since finding out and she has been participating in research studies. She was attending the meeting on her own and she agreed to send me photos and updates. I appreciate her so much because she allowed me to learn through her eyes. What follows is a summary of the updates she sent me.

the registration table

There was a display of ALS/MND patients from all represented countries, including the awesome Osiel Mendoza from the USA.

Jennifer also sent me a photo of the registration swag.

The swag included the Nature Outlook from which I quoted two weeks ago

And now her report on the first day:

The Opening keynote speaker, Dr. Jeffery Rosenfeld from Loma Linda University, spoke about the need for a new paradigm: the need to define and stratify as done in MS, epilepsy, and headache. Even if lines are drawn wrong at first it’s time to start. He also said that biomarkers are what need to be tracked in clinical trials. The patient’s functional rating scale (FRS) doesn’t give results quickly enough.

Then there were awards:

  • Humanitarian award to the guys that started the ice bucket challenge – Anthony Senerchia, Jr. (awarded posthumously), Patrick Quinn, and Pete Frates. Pete’s mom Nancy accepted the award.
  • Forbes Norris Award to Dr. Merit Cudkowicz of Massachusetts General Hospital (and Jennifer’s neurologist) for her passion in researching and caring for patients with ALS and finding the cure.
  • The Paulo Gontijo Research Award to Marta Van Blitterswijk, MD, Ph.D of the Mayo Clinic in Florida for her work attempting to understand the variability among patients with ALS, including age at which it starts, presence of dementia, diesease progression and survival. Most of her patient centered work has focused on the C9ORF72 mutation.

Then Jennifer sent me this photo of ALS TDI researchers. The two on the right are working on C9ORF72 research

She said the rest of the morning was good, although nothing specific to C9 was covered. The Symposium registration was the highest ever – 1281. The scientific sessions were packed. She even saw people on chairs outside the rooms. She said she thought there were slightly more people with ALS there than 2 years ago.

The first afternoon session had a lot about the nuclear pore membrane and C9ORF72. One of the sessions was about SRSF1 (a protein coding gene and nuclear export adaptor) and C9 as a potential way to block the deleterious C9 while allowing the good C9 to work. They are looking at three potential approaches in fruit flies.

She walked through the posters not during the poster session, because of being too tired – I know I would have been exhausted . She noted one that described ALS as the nice person’s disease, and the poster said it looks like some truth to that because the characteristics that make people with ALS nice may be associated with risk factors in lifestyle and occupation.

She went to the clinical trials session on Friday afternoon.

  • Mastinab – normal progressors with less than a 1.1 decline on their FSR showed a slowing of decline at highest dose. There are reports of study irregularities though.
  • Tirasemtiv failed but a related drug is still in trial.
  • Ibudilast – Jennifer said it was confusing. She said they are hoping it slows FSR decline but it needs more study.

Moving on to the Saturday morning session, there was a hopeful presentation on a mechanism to help drugs bypass the blood brain barrier.

She said the biggest deal was Frank Bennett who is Vice President of Research for Ionis, in Carlsbad, CA, which is one of two companies developing the antisense drug. It is already being tested on ALS patients with the first gene defect identified – SOD1 and Bennett said the trial is going well. He also showed a video of kids with Spinal Muscle Atrophy who have been treated and the results were amazing – they were able to meet developmental milestones that untreated patients never could.

Another takeaway was from a presentation from Dr. Michael Benatar of the University of Miami who has been doing pre-familial ALS research – there may be a biomarker sometime that can detect disease before it is obvious clinically which would be a window for treatment for carriers. That would be very exciting.

C9 ALS normally has an average progression rate, but there are subsets – one where there is little progression for years (10 or more years) and another subset where progression is brutally fast. The doctor who was doing extensive genotyping discovered that these brutally fast progressors have a “rare deleterious variant” of the C9 mutation – they all died within a year.

Jennifer also went to Dr. Nick Maragakis’ presentation on excersise. She said basically supervised exercise (stretching, resistance, or cardio) did not hurt the study group but it not help ALS either. But I know from experience that exercise can help quality of life.

Then on to Sunday, the last day. She said there was lots on basic C9 research. Dr. Marka Van Blitterswelk (who won the research award) spoke about her findings on post mortem studies of C9 FTD with and without ALS. It was all good science and increased understanding. This work could not have been completed without the brave C9 patients who donated their brains, and their brave families.

Dr. Nazem Atassi presented on a PET MRI study which is not C9 specific but he thinks it can be used for smaller, faster phase 1 and 2 trials because it has a strong signal.

Dr. Brown giving the closing remarks

The closing session speaker was Dr. Robert Brown, of UMass Memorial Medical Center in Worcester, MA, who has been studying ALS with a special interest in genetics for a long time. He said the C9 antisense trial will be coming up in late 2018 (although I have since heard it may be sooner, and I hope to participate).

I had two comments from family caregivers from my blog requests before the conference.

The first one is from the sister of an ALS patient in California. He was diagnosed in March with familial ALS. After finally getting approved for Radicava he changed his mind so he could apply for the Nurown Phase 3 stem cell trial, and one of the requirements was to not be taking Radicava in the 30 last days. His breathing is also declining quickly and he won’t qualify for the trial if his breathing is below 60 percent Forced Vital Capacity. His sister would like to see changes in trial criteria. Why should a patient have to give up a promising treatment to participate in research? Of course trials are controlled scientific studies but it can lead to very frustrated patients and families.

I too have had frustrations with clinical trials. Many of them exclude patients with feeding tubes. That makes me think that the drug being tested might not be available to patients with feeding tubes.

Cathy Collet, a patient fellow committee member, reported that neurologists are skeptical about Radicava’s efficacy because of the small clinical trial, but glad to have it in their tool bag. I am taking a break from Radicava treatment to sort out unwanted side effects or whatever is causing my sinus problem.

The next comment was from the daughter of an elderly ALS patient in Canada. She is frustrated by the lack of studies on geriatric patients, and the tools to explain feeding tubes and suction to an 88-year-old. She also has observed that weight loss and slurred speech in the elderly is usually attributed to stroke. Cathy Collet said there was no mention of diagnosis in the elderly, and that is near and dear to her heart because her mother was diagnosed in her 70’s. It is an issue that sorely needs to be addressed.

I am sorry that I was not able to attend but I am so appreciative of Jennifer and Cathy for sharing information.

the end of our Hawaii trip and back home to child proof

On Sunday night Jonika and Ollie went to a birthday party.

all dressed up for the birthday party

Stan and Andy and I went to the restaurant at the Kona Country Club. We had a great view of Keauhou Bay and the dive boats with their lights for manta ray diving.

On Monday, our last full day in Hawai’i, we were treated to a whale watching tour on the Body Glove Boat, which is where Jonika and Chris met when they both worked in the boat.

Jonika and Andy, cousins, enjoying the boat
Ollie with dad Chris

We got very close to the whales, and one even bumped the boat! I saw a baby one swimming next to mom. They winter in Hawai’i for mating and giving birth, then make a beeline for Alaska for the summer. We had a naturalist telling us all about them.

there were Spinner Dolphins swimming around too.

The naturalist told us all about the whales’ mating rituals, and we realized we had the results of the Body Glove Boat mating ritual with us. And we love them.

That night we went out for our farewell dinner at Lava Java, a nice ocean front venue with the sound of crashing waves.

Then Tuesday we packed up and Chris and Jonika and Ollie came over to help us clean up the condo and get packed up. With a very short connection in L.A., we knew we had to pack for an extra day, including my food. We put all our meds and toothbrushes in my carryon bag.

When we got to the airport we didn’t have much time to spare. They were lining up the pre boarders. But they soon announced a delay. And then more delay. And we were in the open air airport in the voggy wind. They kept announcing, “no updates, please continue to wait”. We finally made our way to the enclosed restaurant. And then we saw that something had been announced. Stan went to find out. I saw the flight crew leaving as Stan came back and said the flight was canceled. American would put us up at the Hilton Waikiloa with meal vouchers and taxi vouchers. We and all the other passengers had to stand in line for our vouchers and to rebook. We were talking to the people around us and we made a new friend, Anssi from Finland. He had been there for an IT convention. The agent found us a flight the next day on Alaska Airlines which would get us home that night. Our original flight was rescheduled for 4 pm the following day which would get us to Los Angeles after the last flight to Reno.

We rode in a great taxi for the 1/2 hour ride up to Waikiloa. The driver was the owner of a fleet and he said he or another driver would pick us up at 10:30 the next morning.

Our room was on the ground floor right in front of the dolphin pool. Andy called Chris and he said “Sweet!” and said he and Ollie would come early to swim.

We had dinner in a sports bar and Anssi walked by so we invited him to sit with us. We learned a lot about him and Helsinki. He is a sailor and a skier like us. He had been to Reno for gambling and skiing at Squaw Valley. He learned a lot about us too! We will keep in touch.

The next morning Chris and Ollie showed up bright and early. We went to brunch on American Airlines dime.

Then Andy and Chris and Ollie went swimming and Stan and I packed up. On the way out of the hotel there was a man with a parrot.

Our taxi was waiting at 10:30 AM.

And then we flew off the island.

if you look closely, in the distant left you can see snow up on Mauna Kea

Then we finally arrived home and had a few days of sleeping late on Hawai’i time. We also had to do major baby proofing because Jonika and Ollie will be here on January 16, coming to stay with us for a month. Jonika was shaken by Stan’s septic shock as we all were, and we were all reminded that life is short.

Jonika’s best friend, Lyndi, has a son the same age. Jonika said Ollie and Landon meeting will be a dream come true.

they made it! a quick lunch after 2 long flights overnight

I was hoping that my sinuses would clear up by getting out of the vog. But they are still draining. I hope to see an Ear, Nose, and Throat doctor soon.

I also started my fourth round of Radicava and my motion sensors for the precision medicine program arrived. I do have to spend a lot of time managing my illness, leaving little time for pleasure things, like knitting or playing piano and I wonder when I will be able to go back to aqua fitness. I decided to pick up my knitting and the meditative aspect of helps me ignore my sinus problems. I posted a long time ago that ALS is a disease of ch-ch-ch-ch-changes. And life is full of the same.

Even Sue, the T Rex from the Field Museum in Chicago, where Stan and I both saw her as kids, is visiting Reno at our Terry G. Wells Discovery Museum.

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

Island life and ALS

On the Big Island of Hawai’i we enjoyed our grandson immensely.

photo by Jonika

And it was so nice to spend time with Chris and Jonika too.

I had a little snafu on New Year’s Eve – my suction machine broke. And it being Sunday and New Year’s Eve, no medical supply companies could be reached and wouldn’t be reachable until Tuesday. It is lucky I married a MacGyver like guy – he tried to fix the suction machine but he could not – “I could fix this if I was at home.” So in true MacGyver fashion he hooked it up to the vacuum cleaner so I could use it. It gave me an appreciation for the ALS patients in Puerto Rico and other islands after the devastating hurricanes. They were left in a worse state than I was – not a broken motor with a McGuyver guy around but no power for days. It is truly scary to be without suction when you need it badly.After a nice dinner at our condo with Jonika, Chris and Ollie; Andy decided to break the rules and swim after sunset on the last night of 2017.

Then he stayed up to watch the fireworks from the condo deck. But he is the only one.  Stan and I hit the sack before even midnight in Chicago. But I was up at 3 AM coughing and I saw the moonlight on the deck.

the now 2018 moon.

I did not feel I could turn on the vacuum at that hour of the night, because most condos had windows and sliders open. So I took some benadryl and went back to sleep. But I used the vacuum cleaner suction quite a bit on New Year’s Day.

Stan and I took it easy on New Year’s Day. But in the afternoon Andy walked to the pretty, rocky beach down the street.  He called to report that the waves were big.  So he came back and in the waning light of the first day of the new year we drove to Magic Sands Beach. Andy and I ventured into the water.

photo by Stan

I watched him bodysurf a couple waves and then I dove to ride one myself. But I forgot to close my mouth and got a mouthful of salty sea water. I came up coughing – not having a working epiglottis I can’t protect my airway. Plus I haven’t had salt in over a year, so it was very salty in my mouth. A woman asked if I was ok and Andy came over to help me.

photo by Stan

I bent down to write in the wet sand to tell Andy what happened.

photo by Stan

We walked back to where Stan was sitting on a rock.

photo by Stan
photo by Stan

After sitting a few moments, Andy and I went to rinse off in the outdoor shower. When we got back, I sat for a few minutes and realized that I had just done a natural netti pot – my sinuses were draining mightily. So we had to go back to the condo so I cough assist and use the jerry rigged suction. Then I slept for an hour but had to get up at 8 pm to eat dinner. I woke up coughing at 2 am and not being confident of sleeping with such irritated lungs or willing to turn on the vaccuum cleaner with all the windows open in the neighboring condos, I stayed up and finished my book. But at least I went in the ocean and it was exciting before scary.

It wasn’t until Tuesday after the holiday that we could work on a replacement for the suction machine. Our home Durable Medical Equipment (DME) company Bennett arranged for a machine from a Big Island DME.  It was delivered Wednesday. It is not portable.

It is heavy and has no case. And we are supposed to carry it back with us so Bennett can ship it back to Hawaii. So Stan called the company but all he got was a run around and voicemails. I texted our rep from Bennett and she had the local DME call Stan. He got a call back Thursday morning saying the DME didn’t have a portable suction machine. But they said they will look for one.

We went to the Hulihe’e Palace with Jonika, which we had not seen before.

This historic home was built in 1838. It belonged to the governor of the island of Hawai’i. When his son married into Hawaiian royalty it became a favorite retreat of royal families. It houses a collection of ancient Hawaiian artifacts and personal memorabilia of 19th century Hawaiian royalty, including beautiful koa wood furniture and bowls. There was also ancient jewelry and weapons. There was a very entertaining guide upstairs.

The view out of one of the first floor rooms.

After the palace tour we had a nice lunch in a new restaurant that Jonika had wanted to try.

the beautiful flower adorned food

Still dealing with mucous, I tried a medrol dose pack and a stronger antibiotic. I also had to refill my Xanax which I take for ALS anxiety which is a very real thing, especially after watching my mom go through it. I had a refill from my Reno doctor but in Hawai’i for controlled substances, only prescriptions written by Hawai’i doctors can be filled. So we went to urgent care Tuesday night and got the prescription – and will have to send the bill into our insurance company. And then we went to dinner.

a dinner conversation about 2018 expectations and goals

Another night we had a nice dinner at Jonika’s house with friends of theirs from Portland, Oregon. Jonika and Mike have been friends since riding the bus to middle school and high school from our house – he lived around the corner from us. Jonika made a pumpkin soup in a pumpkin that I heard nothing but raves about.

While Stan and Jonika were grocery shopping for the dinner party, Stan got a call from the DME that they had a portable suction machine, so they went and picked it up. It is the best suction machine I have had yet.

We babysat for Ollie quite a bit. He is a sweet helpful child until he is tired and I think he is growing this week – he is sleeping a lot and we see him learning new things.

Jonika’s work on phones for Seaquest, the boat company she works for, is wonderfully flexible. She can be at home or wherever and just has to answer phones and book trips on her iPad. She can get things done between phone calls. She can do this work in Reno too when she visits later this month. She also works in the office and does sales presentations for the company.
Despite his lethargic parents, Andy had fun. 

Chris took him  cliff diving (video by Chris):​

And Jonika took him zip lining.

Andy and I took Ollie to the pool.

It was a week of love, connection, and hope – hope that my sinus mucous would clear up. I could be reacting to the vog which is gases from the volcano. Vog and dogs and cats and pollen – my body reacts to the world I live in and I may be managing mucous the rest of my life. Allergies and sinus infections used to be  minor inconveniences but now I can’t blow my nose or cough or swallow well but I am still hopeful the problem will clear up, and in the meantime I will pick my nose and hack into cough assist and suck out mucous with suction and be thankful for electricity.

Holidays, family and friends: love and connection

We spent Christmas with Stan’s dad and step mom, Cathy.  Stan left for Las Vegas five days before Andy and me. He drove down towing our RZR side by side in order to spend a few days taking his dad off road. His dad has loved hiking and getting out in the wild his whole life, but due to his health he has not been able to go out.

Stan texted me this photo and it was wonderful to see John out in the land he loves.

They had a great time for three days exploring the hills near Vegas.

Andy and I flew down Friday night after Andy finished finals. We had a nice visit. There are four dogs in that house and I was bothered by an allergy to the dog hair. I know I talk a lot about allergies in this blog, but with Bulbar ALS at the extent I have it, it is a big problem. I can’t swallow or cough or blow my nose. The week before Christmas I realized my symptoms were indicative of a sinus infection.  My awesome nurse practitioner called in a Zpac for me, and then a second one. And it was still with me.  So she called in Cipro for me. I started to feel better, but the intense dog allergy made it hard to know if the antibiotics were working.

Stan had a bout of food poisoning while we were in Vegas and was sick for a day. But for once he got sick and didn’t end up in the hospital. 

Andy helped Grandpa by picking all the ripe lemons off the tree in the back yard. They were posing for a photo, both holding handles on the bag when it broke.

On December 23, Stan’s step mom Cathy’s friend, Sandy, came over and we had a nice visit. 

Andy even played his viola for all of us.

Grandpa was a great music holder

Christmas was a nice gathering of my inlaws’ friends. The guests all were impressed with my text to speech app on my phone with my wireless keyboard and my Boogie Board too.  We shared stories and laughed. 

Stan gave me some gifts that will help me deal with my ALS. One is a charging cellphone case. I use my phone to speak so by mid afternoon my battery is already running low. I have tried external batteries but they are cumbersome and the charger connections don’t last long. Now I can charge overnight and both phone and case charge and in the morning the phone is charged and when the charge goes down the phone case takes over charging it. So my charge now lasts all day. It is wonderful. Another thing is a pill grinding syringe.

It has a grinding surface at the bottom of the syringe, so you can grind a pill or pills right in the syringe with the plunger. It works best to suck in some water and suspend the ground medication in an aqueous solution. Then it can go right into my stomach through my Mic-key Tube.

The day after Christmas we drove to Kingston, Nevada to visit our good friends, Ann and John, at Miles End Bed and Breakfast. This was the end of their Christmas brèak. They had just returned from Carson City that afternoon. We were the only guests and they brought pizza from Carson for dinner. That was fine because we were there as friends, not B&B guests. 

Long time friends Ann and Stan talking while Zee enjoys a Christmas present of dog biscuits.

But in the morning, Stan and Andy enjoyed John’s normal wonderful breakfast. Ann had to run off to work at the clinic, which she runs. So we packed up, said goodbye to John, and stopped by the clinic to say goodbye too Ann.

Andy drove us home and we got home mid afternoon.  We had to unpack, do laundry, and pack for another trip – this one to Hawai’i. But we were able to have dinner with my sister Cathy and Rick and 10-year-old Sam, visiting from Portland, Oregon. It was too bad that was all the time we had to visit. It was also too bad I was so tired I didn’t even take photos. But here is one they texted from San Francisco a few days later.

Then we flew to Hawai’i. I was worried about needing cough assist and suction on the long flight. But I went and talked to the flight attendants in the back and asked where I could do it. They asked if I could use the bathroom. I said no, too small. Then they offered me the back row of the plane (their seats) while they did beverage service. That worked out great because it was so loud back there that no one noticed me coughing with the cough assist or suctioning and both are loud.

Our niece who we raised lives on the Big Island and her son Oliver is 18 months old. We are his ‘grandparents’ and so proud of this handsome, smart boy (spoken like every grandmother😎).

Andy and Jonika have a bond closer than cousins. And Andy has a special bond with Ollie too.

We had a crazy surreal and funny dinner at a restaurant that will not be named. The waitress had real difficulty with our order, bringing the wrong things and totally forgetting one meal. But it was very fun and I was told the food that did come was great. 

Chris and Stan
Headstrong Ollie saying no to mom

Chris ended up getting his food to go. That led to jokes that may continue the whole trip – like ‘we could go back to that restaurant – but we might want to eat before we go!’

My morning view on December 31, 2017. The ocean is in the distance on the right.
New Year’s Eve 2017 (photo by Chris Grossi)

I had lots of love, connection, and hope in 2017 and I am looking forward to lots of the same in 2018 too. I hope you find the same.