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How rare is rare? And other common FAQs on “Rare Disease Day”

To mark Rare Disease Day 2018 (Feb 28), we repost this explainer from DNA Science blogger, geneticist and rare disease specialist Ricki Lewis to address commonly asked questions about rare diseases. —PLOSBLOGS


According to the  National Organization for Rare Disorders, “rare disease” in the U.S. means affecting fewer than 200,000 people. These conditions number about 6,800, collectively affecting nearly 30 million Americans or 1 in 10 people.

Many rare conditions are single-gene diseases. That means that the chance of more than one family member being affected is quite high (see Mendel’s first law). Unlike those, most (>90%) cases of ALS and breast cancer aren’t inherited as single-gene traits, but are sporadic. Mutations happen during a person’s lifetime in somatic (b0dy) cells, perhaps due to an environmental trigger. A family with sporadic ALS wouldn’t have to worry too much about the patient having passed it to a child; not so a family with Huntington disease.

With many causes of rare diseases, comparing statistics is an apples-and-oranges exercise. But I collected a few anyway, for prevalence (the percentage of a population with a particular disease at a given time).

Breast cancer (all types) affects 122 in 100,000 people. ALS (all types) affects  3.9 per 100,000. Absolute numbers are more meaningful for the rarest of the rare. For example fewer than 100 people worldwide are known to have giant axonal neuropathy, which is similar to ALS in a young child. But unlike ALS, the chance of a sibling of an affected child also inheriting the condition is 1 in 4. Thanks to exome sequencing, even “one-of-a-kind” individuals with strange constellations of symptoms that defy shoehorning into known diagnoses are being understood. The exome kids are tantalizing to journalists (see the New Yorker.)

But so very many diseases aren’t chosen for the New Yorker, or don’t have a Lou Gehrig or Joan Lunden materialize.


I had mixed feelings about the ice bucket challenge (henceforth “IBC”) for ALS, noting how few people have read my posts here about the disease, compared to important posts like how Dan Brown screwed up genetics in his latest bestseller. So I polled the rare disease families I know about the IBC, and boy did I strike a nerve! They share awe at the brilliance of it, joy at how much was raised for ALS, surprise, and a bit of envy.

“People associated with other diseases became really upset, probably because they wished they had thought of it. It took on a life of its own, and then it just abruptly stopped when people became tired of watching endless videos, and that caused a backlash,” said Ilyce Randell, president and co-founder of Canavan Research Illinois. The organization’s major annual fundraiser celebrates son Max’s birthday — he’ll turn 17 later this month. I’ve been to two of them. (Canavan prevalence: about 10 in 100,000.) This post chronicled Max’s brother Alex’s efforts to fight brain disease.

Laura and Taylor, in happier and healthier times.
Laura and Taylor, in happier and healthier times.

Laura King Edwards is running races in all 50 states to raise awareness and funds for infantile Batten disease, which has robbed her 16-year-old sister Taylor of her sight, mobility, speech, and ability to eat. Laura took the IBC and attempted to extend its reach.

“I did try to post some more educational/advocacy-related links on the Taylor’s Tale Facebook and Twitter pages. Those posts didn’t get much response. People didn’t want information with meat to it – they wanted to watch entertaining videos of their friends. That’s where our challenge comes in – how to identify strategies that are sustainable. Because if I know anything, it’s that the fight against rare disease won’t be won overnight,” she said. (Prevalence of all forms of Batten disease is  2 to 4 of every 100,000).



The IBC seemed to have gotten under the skin, in one way or another, of nearly everyone I contacted.

“We didn’t pay much attention to it, and did not accept the challenge from anyone. We kept the focus on our goal,” said Jennifer Pletcher, whose daughter Finley has Leber congenital amaurosis (LCA) caused by mutation in the RDH12 gene. “Some people actually did the challenge and donated to our foundation, which was cool,” she added, pointing out that October is Blindness Awareness month too. See (Prevalence of her daughter’s condition: 10% of the 2-3 per 100,000 who have any of the 22 genetic forms of LCA.)


Ilyce Randell echoes Jennifer Pletcher’s focus on her family’s disease. This isn’t being selfish, it’s using genetic logic. While rare disease umbrella organizations are enormously helpful in sharing information and strategies, funding clinical trials is a different matter.

Testing a treatment for a single-gene disease requires participants who share mutations in the same gene. Finley Pletcher’s LCA is due to mutation in a different gene than the one that is mutant in Corey Haas, the boy at the heart of my book The Forever Fix. His successful gene therapy targeted his RPE65 gene.

Campaigning to treat all forms of LCA, or all forms of Batten disease, is useful in addressing shared concerns, but might dilute the financial power needed to get a phase 1/2 clinical trial off the ground, or support the daunting cost of a phase 3 trial necessary for FDA approval for marketing.

“Fundraising/awareness campaigns are more effective when we do not try to unite every similar disease. Parents of children affected by Canavan who raise money and direct it to a blanket organization are often times not helping advance research for their own child. We’re raising money for the only researcher who has ever worked with living Canavan patients in a clinical setting. But there are families raising money for ’research’ for ‘allied diseases,’ organizations that do not even fund her work. When it comes to curing my son I’m not in a true alliance with any other disease because all funding is scarce, and different diseases are competing for the same federal funds,” shared Ilyce.

And that competition is fierce. Just two days ago, the U.S. Food and Drug Administration (FDA) announced “awards of 15 grants worth more than $19 million to boost the development of medical device, drug, and biological products for patients with rare diseases.” Six are going to cancers, 2 to infectious diseases, 4 to others that aren’t inherited, and of the 3 that are, two are for sickle cell disease and one for cystic fibrosis – classic textbook genetic diseases. “You have an easier time asking for money for something people have heard of,” said Ilyce. SavingEliza - instagram

Glenn O’Neill is more enthusiastic about the IBC, perhaps because his family’s efforts to “save Eliza” from Sanfilippo syndrome also went viral, before the ice buckets descended . They adapted the “challenge” part of the ice bucket craze.

“On August 12th we started our #Sing2Lines to stop Sanfilippo challenge based on Eliza’s love of music and the fact that she can still sing. You post a video of yourself singing 2 lines of any song, and challenge 5 friends, to give Eliza and other children a voice, and a chance at life,” Glenn said.

They’ve sung their way to more than $75,000 with thousands of entries, including one from actress Andie MacDowell.


For the rarest of the rare, fundraising efforts are usually family-run, all volunteer. This is not often the case for more common conditions. When any disease organization calls for a donation, it’s a good idea to ask how much of what you donate actually goes to research or patient support. Check out Charity Navigator.

A caller for a large breast cancer organization had the misfortune of getting my husband on the phone last October. Larry volunteers for several not-for-profits that do not pay fundraisers or anyone else, and he immediately interrupted the script to ask whether said organization paid the people who made the phone calls. Yes, they did.

But breast cancer is so common! You must know someone who has it!” insisted the paid caller.

If it’s so common, why can’t you get volunteers to make the phone calls?” Larry asked.

Laura King Edwards weighed in with “Pink for One Heck of a Price Tag” two years ago, noting that the NFL shelled out $5 million on ads and paraphernalia for their breast cancer awareness blitz. “If I could write a $5 million check to the world’s best Batten disease experts, I believe in my heart that they’d give us a treatment that works,” she wrote.

Others chimed in on the cost of fundraising issue. “For Finley’s Fighters, 100% goes to research. We don’t have overhead cost or paid employees. We rely on sponsors for our events and all other costs come out of the family’s pockets,” said Jennifer Pletcher.

Michael and Mitchell Smedley and their friends brainstormed the Bike the Basin event.
Michael and Mitchell Smedley and their friends brainstormed the Bike the Basin event.

Kristin Smedley, who has two sons with the CRB1 form of LCA, agrees. “I let my supporters know that our fundraising does not pay salaries, it does not pay for office space, it does not pay for public relations firms to get me on TV. We are all volunteers here working out of our kitchens.”

Their annual event, Bike the Basin, raises enough funds to sponsor an annual research meeting for their CRB1 (Curing Retinal Blindness) Foundation– I attended the first one.

I’m not insensitive to the challenges of cancer. I had it. And I watched my mother undergo treatment for metastatic breast cancer. But an entire month of “raising awareness” for breast cancer? Who, exactly, hasn’t heard of it? And who is being ignored as a result?


Of all of the inspiring rare disease family members I’ve “met” during my writing journeys, the most spellbinding is Jacey Mukka. She turns 22 later this month; she didn’t think she’d live past 21.

Jacey has juvenile Huntington disease (JHD). With prevalence 5% of the adult version’s 5.7 cases per 100,000, there isn’t much interest. lists only one trial, from the European Huntington’s Disease Network, that tracks kids who have symptoms, rather than still-healthy at-risk individuals who’ve inherited the mutation. For another apples-to-oranges comparison, I entered “glioma,” the type of brain cancer that’s just received 3 of the 15 grants from FDA, into 1,439 hits to JHD’s lone one.

Karli, Jacey's little sister.
Karli, Jacey’s little sister.

Jacey’s dad and little sister Karli passed away from HD; Jacey’s older sister has it too. Jacey is very ill, but I don’t want to dwell on her body here. Details are in another post. Instead, I’d like to share her thoughts.

I promised myself when I was younger I would die before my little sister, I would die before my father, I would die if I ever got the temper of my father or started hurting people.

But that didn’t happen. Karli died at age 13, in 2010. Jacey remembers.

Reality still hadn’t hit, until the nurse came in. She said to come say goodbye. No it’s not possible, it can’t be. I went into her room and I saw her lips were blue. Mom and Erica snuggled up to her and she took her last breath. She was free. It hurt worse then I thought ever possible, just hold her bunny and curl up on the couch and cry until you run out of tears, and cry even after that. We gave Daddy her pink rabbit and he held it as tight as he could, and then he died 2 months later.

Jacey started after hearing families talk about having children even though a parent has the HD mutation, because “the child wouldn’t get sick until it was older and by then they’d have a cure.” Jacey sends hugs and books to the friends she’s made, and raises funds to help them get through life, one day at a time. The website is full of facts, stories, and ideas. And it is vital, if only to a few, because no one’s dumping ice to draw attention to JHD.

I wish the ice bucket challenge had brought more recognition to the hundreds of rare genetic diseases that lie so under-the-radar. Far more lasting than the ICB is Facebook, where I hear daily from my “families.” Facebook connects the individual efforts that are so important to conquering the single-gene diseases, one at a time.

  1. Your blog really hit home. We did the IBC with a twist giving recognition to our boy’s rare disease which has similarities to ALS. Our three sons have a very rare genetic disease called Fahr’s Disease. Only 60 families in the world are documented to have it and there are no clinical trials. Only one researcher in Brazil is still looking into it. Three genes have been identified but that only accounts for 20 percent of those diagnosed. Our gene is still unknown. Even more rare with Fahr’s is to have children with it and we have three. Three of only a handful. A year ago we started the Fahr Too Strong Foundation to promote awareness, create a support network, and educate doctors and sufferers. Many who have gone through their life unaware of the genetic component and now are realizing several generations in their families are affected or will be. There is a 50/50 chance to pass it on. Our foundation is completely run by volunteers and we have struggled to get the word out there.
    We commend your work and words. Thanks for saying what we have been feeling.
    Suzanne Leypoldt

  2. You hit the nail on the head with me! I have a very rare syndrome (estimated at 1 in 100,000 in the general population) called Hypophosphatasia (HPP). Caused by very low production of the enzyme alkaline phosphotase, it seems to affect each of us who has it somewhat differently, though there are similarities. The main symptom seems to be soft bones. Some babies are stillborn because they do not form real bone in utero; rather, it is more like cartilage. Theirs is the most severe. Some babies and young children suffer frequent fractures and extreme respiratory problems. Many die very young. Then there are others like my mother who has Odontohypophosphatasia which affects only her teeth.

    My son and I have what some call the “adult form”; we lost our baby teeth at about 15 months old, and have lifelong severe dental problems. (Believe me, no one helps pay for all those dental procedures!) Then in mid-adulthood, we begin to break bones very easily and then get frequent stress fractures in the metatarsals of our feet that take months and months to heal. Eventually, the stress fractures extend to the femurs and hips.

    I find myself very blessed because I was the last person to be admitted 3 1/2 years ago to take part in a research project for a new, very effective enzyme replacement therapy. The only reason the gene was discovered in 1949 in Canada and now this experimental med has come into being is because the Mennonite community there has intermarried so much. Their incidence of HPP is 1 in 2500! I was born in 1953 in Oklahoma, and I had no knowledge of HPP until my son’s baby teeth began to fall out. Even then, I didn’t know it was affecting my bones and very possibly other areas as well. If not for the Canadian Mennonites, we most likely still would have no idea what was wrong.

    HPP merits one brief paragraph in medical textbooks on metabolic diseases, and I have yet to meet a local doctor or dentist who has ever heard of it. I diagnosed myself after numerous fractures, with benefit of the internet and an online yahoo support group, about ten years ago. Fortunately, I already had and still have a wonderful internal med doc who allowed me to educate him!

    My son and I have never had genetic testing. Who would pay for it? But I dearly hope my son will benefit from this new drug some day, hopefully before he begins to get fractures. He does his best not to think about it.

    I have friends with children who have much more severe, fatal genetic diseases, such as NKH. They do their own fundraising, and I pray for them and their families daily. I also have two longtime friends my age who suffered breast cancer in their mid 40s; one has little time left after a very long, hard road. My mother’s sister also struggled with it. Still, I find it hard to accept that breast cancer merits more research funding than diseases like NKH or HPP, especially for children. Just because they are fewer doesn’t mean their lives aren’t as valuable or their and their families’ suffering as great and often much greater.

    Thank you so much for this article!

  3. Thanks so much for sharing your story Lucretia, you told it better than I ever could. And I have heard of your condition, it is in my textbook somewhere, but I didn’t know it was so incredibly rare. I suspect that you had a genetic test when you were in the trial for the medication — do you know? The researchers would need to know that to target the ERT, which I’m sure is or will be quite expensive. Good luck to you and your son! And thanks for writing.

  4. Thank you for saying so well what has been on my mind. I have nothing against breast cancer awareness, I lost my mother, grandmother and 2 aunts to breast cancer. But, honestly we have many rare or invisible diseases that need attention. I have Addison’s disease, lupus, fibro and a basket full of other conditions. Finding an endocrinologist who knows how to treat Addison’s is beyond difficult. The US has done next to no research on it. Hospitals & emergency response don’t even know what to do for us when we go into adrenal crisis. Many people with Addison’s die because of this. For everyone with a rare disease, I pray for answers and awareness.

  5. I hate disease fundraisers. Who is ever going to walk for mastocytosis? Sickness allocation shouldn’t be a popularity contest. Utilitarianism in dease only seems to work work when it isn’t *you* that’s affected by a rare disease. I hate sexist, smarmy pink. I hate the whole fundraising dynamic.

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