DNA and Dating: Buyer Beware

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128px-Emoji_u1f4b0.svgLast week’s post dealt with three very serious types of DNA tests. But not all DNA tests detect health-threatening conditions.

A few years ago “Born to Run? Little Ones Get Test for Sports Gene” ran on the front page of the New York Times, above an arresting image of a preschooler having his mouth swabbed for DNA. It’s from 2008, but remains a classic: I still assign it.

800px-FPYC_Soccer_-_02The sports gene company tested for variants of one gene, ACTN3. Two copies of the R577X variant indicate inborn skill at endurance events, and no copies suggest a child stick to sprints. The lucky heterozygotes might excel at both! Never mind that a child has some 20,000 or so other genes affecting physiology.

DISSECTING A DNA DATING WEBSITE
The most damage a sports gene test can do is to keep a child from something she loves because of a DNA-obsessed parent. A more questionable application of DNA testing is in “relationship science,” something I learned about a few weeks ago when a reporter from healthline.com asked me about it. And so I perused the website of the “leader in human genetic compatibility.”

The company offers tests for four genes. Three are members of the human leukocyte antigen (HLA) complex, which encodes the cell-surface proteins that determine who can give body parts to whom and reflects many disease susceptibilities. The fourth gene, SLC6A4, encodes a serotonin transporter.

Both the HLA genes and SLC6A4 have been studied for decades. Yet the test panel doesn’t include ancestry markers, which I think might be more important in mate selection than tissue compatibility.

Wasps get it on. (Elizabeth Cash/John Gibson)

Wasps get it on. (Elizabeth Cash/John Gibson)

HLA TYPING
The company is using HLA typing as a surrogate for scent, claiming that 40% of olfaction comes from the genes. But the existence of human pheromones is still under debate, although they were predicted to exist half a century ago, and many a website will happily sell you some. (The image shows tiny wasps with the wonderful name Nasonia vitripennis mating, thanks to pheromones wafting from the male.)

More telling in the scent department may be the 1995 study of women preferring the sweaty T-shirts of men least like them genetically. Wikipedia credits it with starting the field of genetic matchmaking.

Why wouldn’t humans have pheromones, when so many other animal species do? Plus the HLA genes are so involved in biological compatibility that I suspect they indeed have something to do with scent and pheromones. But do we need a DNA test to tell us when a potential date stinks? Maybe so. That’s one characteristic we can’t yet inspect on our electronic devices.

Bone_Marrow_TransplantKnowing one’s HLA type is not without value, but its hard to say whether one should seek a mate with a different or similar profile. People with different HLA variants may be less likely to pass infections back and forth. But couples with similar variants would be better off if one of them needs a blood transfusion, bone marrow transplant, or part of a liver.

THE SEROTONIN TRANSPORTER
SLC6A4, which encodes a serotonin transporter, is also a logical choice for a dating gene. Like the HLA genes, its variants are associated with several health conditions: sudden infant death syndrome, Alzheimer aggression, depression following emotional trauma, alcoholism, neuroticism, deviant sexual behavior, hypertension and obsessive-compulsive disorder.

(Dr. Yoichi Araki)

(Dr. Yoichi Araki)

The SLC6A4 protein recycles the neurotransmitter serotonin to the reuptake stations on presynaptic neurons in the brain. Serotonin is what’s theoretically scarce in some cases of depression (like pheromones, that hasn’t been definitively shown either), and so the transporter provides a target for the “selective serotonin reuptake inhibitors” like Paxil. It’s also the target of the older tricyclic antidepressants, as well as amphetamines and cocaine.

People can have a short version or a long version of one part of the SLC6A4 gene. In one study, people with two short variants self-reported future dissatisfaction with their marriages if they previously reported high or low emotional behavior (whatever that means). Conversely, if people have at least one “long” version of the serotonin transporter gene, then their emotional behavior does not influence their perceived long-term stability of their marriages.

What the serotonin transporter has to do with dating is beyond me, although I have not dated in centuries. But I think a shared love of dark chocolate, running, and binge-watching Orange is the New Black may be more meaningful measures of day-to-day compatibility than SLC6A4 genotype.

Testimonials on the company’s website attest to the fact that people do believe that choosing dates based on limited genotyping has value. They are falling into the trap of genetic determinism, the idea that DNA is destiny.

Valentines_Book_1940_1“We knew the test would show a great match because we knew we had chemistry when we met. We think the test results show that the Instant Chemistry DNA test can help singles find that person who they have a real connection with,” writes one satisfied customer.

I emailed the company requesting data showing that people with particular genetic profiles are more likely to be compatible, and how the company defines and assesses compatibility. I haven’t heard back yet. However, a news release from July, prompting a flurry of media coverage, informed us that the company is “proving that there is science behind attraction,” with “new, groundbreaking research.” So stay tuned.

ATCG's Image with Group of PeoplePRECEDENTS

Using genetic testing in mate selection is a decades-old strategy. Dor Yeshorim is a program that originated in the Hasidic Jewish community in New York City. It has tested thousands of young people from all over the world for several “Jewish” genetic diseases since a rabbi who had children with Tay-Sachs disease started the program in 1983. Testing is anonymous, using numerical identifiers, and carriers are not told what they carry – just whom to avoid having children with, if they so choose. Their testimonials are the plummeting incidences of some of these diseases in the tested population.

800px-Foundation_(cosmetics)At the other end of the seriousness-of-genetic-testing spectrum, federal regulators are finally cracking down on dubious DNA-based claims. Two years ago I’m embarrassed to admit that I bought “age-defying with DNA advantage cream makeup” because I couldn’t resist the goop in the see-through container swirled into a double helix shape. I’d thought I’d read that FTC had made these genetics references in cosmetics ads disappear, but they forgot to tell Google.

Adding “DNA” to skin cream ads doesn’t really hurt anyone. But making medical claims is a different story.

My favorite study exposing misuse of genetic testing is from the U.S. Government Accountability Office, like the sports gene flurry also from 2008, when  direct-to-consumer genetic-testing debuted. GAO investigators submitted DNA samples from a 9-month-old girl and a 48-year-old man to four “nutrigenetics” companies, but with 14 made up lifestyle/dietary profiles. None of the companies, which offered dietary suggestions and pricey packages of exactly the supplements that an individual purportedly needed to avoid her or his genetic fate, bothered to do a health history.

Lo and behold, the advice from the four companies tracked with the made-up backgrounds and not genetics. And the results reported on very common conditions (to which genes may contribute minimally) and stated the obvious, like not smoking. Concluded the study: “Although these recommendations may be beneficial to consumers in that they constitute common sense health and dietary guidance, DNA analysis is not needed to generate this advice.” Some of the suggestions could even be dangerous, such as vitamin excesses in people with certain medical conditions.

640px-Snake_oil_or_Memory_Elixer_anyoneI don’t know if the FDA, FTC, or GAO are interested in a dating website that preys on those who don’t know much about DNA. My advice for deciding whom to date? Talk to people! Don’t shell out hundreds of dollars to learn about a handful of genes.

(Some of this material comes from chapter 20, Genetic Testing and Treatment, in my textbook Human Genetics: Concepts and Applications, just published by McGraw-Hill in the 11th edition.)

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Genetic Testing For All: Is It Eugenics?

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ATCG's Image with Group of PeopleIn recent weeks, there’s been talk of three types of genetic testing transitioning from targeted populations to the general public: carrier screens for recessive diseases, tests for BRCA mutations, and non-invasive prenatal testing (NIPT) to spot extra chromosomes in fetuses from DNA in the maternal bloodstream.

Are these efforts the leading edge of a new eugenics movement? It might appear that way, but I think not.

(NHGRI)

(NHGRI)

When I began providing genetic counseling 30 years ago at CareNet, a large ob/gyn practice in Schenectady, NY, few patients were candidates for testing: pregnant women of “advanced maternal age” (35+), someone with a family history of a single-gene disorder or whose ethnic background was associated with higher prevalence of a specific inherited disease. Their risks justified the cost and potential dangers of the tests.

Now the picture is rapidly changing as plummeting DNA sequencing costs and improved technologies are removing economics from the equation. It’s becoming feasible to test anyone for anything – a move towards “pan-ethnic” genetic screening that counters the “sickle-cell-is-for-blacks and cystic-fibrosis-is-for-whites” mindset.

So here’s a look at three very different types of genetic tests that are poised to make the leap to the general population. And despite new targets revealed with annotation of human genomes, some of the detection technologies themselves are decades old.

sickle#1: CARRIER SCREENING
Population screening for carriers of single-gene diseases has been around since those for sickle cell disease and Tay-Sachs disease in the early 1970s. We learned a lot from their starkly different results. For years, labs such as Athena Diagnostics, the Baylor College of Medicine Medical Genetics Laboratories, Emory Genetics LaboratoryAmbry GeneticsGeneDx and  others have added genetic tests to their rosters, which now cover hundreds of single-gene diseases, from A (Alport syndrome) to Z (Zellweger syndrome).

HORIZONlogo(CMYK)Other companies have recently visited CareNet, pitching tests for more single-gene diseases for everyone. For example, Natera’s Horizon Carrier Screen tests for 39 conditions and 127 variants of the cystic fibrosis (CF) gene. They provide genetic counseling by phone, which is common these days, given the scarcity of trained genetic counselors, especially outside cities. And Natera can tailor screening panels to specific populations.

In addition to the changing economics, the public is more familiar with DNA-based tests, partly due to the direct-to-consumer testing company 23andMe. Before FDA forbade them from selling carrier tests as “information,” thousands of people learned about recessive diseases from the company’s excellent website.

Cystic fibrosis illustrates the widening of test offerings. Carrier screening began in 2001 for whites and Ashkenazi Jews, following recommendations from the American Congress of Obstetrics and Gynecology and the American College of Medical Genetics. By 2005, with many more mutations identified and the diagnosis broadened, testing expanded to everyone. At CareNet every pregnant patient gets a CF test, along with a factsheet that I wrote.

counsyl-logo-largeCF is just one gene of thousands. Researchers from Counsyl, another newer player, published a key paper reporting on 23,453 patients from ob/gyn, genetics, and infertility clinics screened for 108 disorders. Nearly 24% carried at least one disease-associated recessive mutation! 5.2% (1,210) carried 2 or more, and .33% (78) actually HAD a disease by having inheriting two mutations.

Interestingly, stratifying participants by population group revealed the differences that once fueled restriction of testing. Although overall 24% of the total carried at least one disease, that ranged from 6.3% among Native Americans and 8.5% among East Asians to 47.1% among the Finns and 43.6% among Ashkenazi Jews. Only 15.8% of African-Americans were carriers.

#2 BRCA TESTING FOR ALL
BRCALast week in a controversial Viewpoint in JAMA Mary-Claire King and colleagues suggested “that population-based screening of women for BRCA1 and BRCA2 should become a routine part of clinical practice.” These genes normally participate in DNA repair, and mutations raise risk of several cancers, not just the widely-reported breast and ovarian. (BRCA1 mutations predispose to cancers of the cervix, colon, uterus, and pancreas, and BRCA2 to cancers of the stomach, gallbladder, pancreas and bile ducts, as well as to melanoma.)

Results from the first families that Dr. King analyzed, published in 1990, were Ashkenazi Jewish with several affected members, because it is easier to discover a gene and what it does in a population with very few variants. It turned out that this group has only three mutations, all of which obliterate the genes’ vital function. Sequencing the entire huge gene wasn’t necessary, lowering costs substantially.

Based on the 1990 paper and follow-up, for years we genetic counselors would consider the number of cases of the relevant cancers and ages at diagnosis in families. We used published guidelines to decide to whom to offer BRCA testing.

(NHGRI)

(NHGRI)

That approach invariably missed some cases in families that were small or had few female members. We knew that accruing data on populations beyond the high-risk Ashkenazim would take years, mostly because thousands of mutations exist.

Many people thought Dr. King’s suggestion of wider BRCA screening premature. Criticism centered on the experimental design in the PNAS paper that the Viewpoint addressed, also from the King group. It focused on Ashkenazim because with fewer mutations the data were easier to collect, especially back when the study began.

The researchers tested more than 8,000 healthy Ashkenazi men in Israel for BRCA1 and BRCA2 mutations, and then offered testing to all female relatives of the 175 men found to have mutations. These women, it turned out, indeed had very high risks of developing the associated cancers – and about half of them had NO family history. Following the old guidelines would have missed them. (An important caveat in the Viewpoint cautioned that testing should only be for meaningful mutations – not the many “variants of uncertain significance.”)

But we can’t know which mutations lurk in whom unless we look for them! And not testing members of families that don’t fit the original pattern will miss cases. That’s what happened in my friend’s family.

Maya’s son discovered he had a BRCA mutation after he took a 23andMe test, for fun, back when one could do this. Maya was tested next because she’s Ashkenazi, but it was her husband, who’s Catholic and European, who’d passed on the mutation to their son. Fortunately their daughter escaped the family legacy. But here’s a family in which the cancer can indeed begin in either father or son, and in more distant relatives. The affected individuals are now being tested regularly for the associated cancers – no one is running off to have organs removed. A positive genetic screen result — meaning identification of a gene variant, not a diagnosis — signals a need for vigilence and preventive health care. It’s not a ticket to surgery.

(Shendure lab)

(Shendure lab)

#3 FETAL DNA TESTING
Until recently, testing fetal DNA (NIPT) was only advised for pregnant women at higher risk of the fetus having an extra chromosome 13, 18, or 21, the most common trisomies. That is, women over 35, or who’d had a previous trisomy. Soon it will be offered to all.

Entire fetal genomes can be sequenced from DNA snippets in the maternal bloodstream, which are shorter than the woman’s DNA pieces. But whole genomes are, for now, TMI. The first commercial non-invasive fetal DNA tests detect abnormal chromosome ratios or differences at single sites (SNPs) on those chromosomes in both genomes, in high-risk women. By August 2014, the data indicated that NIPT is safe enough for low-risk women.

At least half a dozen companies now offer NIPT. It will clearly save lives.

“The sweet spot is for women who are deciding whether or not to have an invasive procedure because they are at higher risk due to advanced maternal age, a positive screen of serum markers, or a fetal sonographic abnormality. If testing fetal DNA gives an all-clear, at least for these three chromosomal conditions, then the pregnant woman can avoid the risk of a more invasive procedure, such as amniocentesis,” Diana Bianchi, MD, professor of pediatrics at Tufts University, told me.

Dr. Bianchi  is the mother of the invention, described in this DNA Science blog post. She reported detecting cell-free fetal DNA and suggested noninvasive prenatal testing back in 1996. “Nine to one, women want the blood test first, and a great majority of them have a negative result, so they don’t go on to have amnio or CVS,” she added.

But that benefit wasn’t immediately obvious to critics unfamiliar with the spectrum of prenatal testing options. Dr. Bianchi received threats from people who saw testing fetal DNA as a way to avoid the births of people with Down syndrome and the other trisomies.

Eugenics_congress_logoIS IT EUGENICS?
Eugenics is “the science of improving a human population by controlled breeding.” Mention of the term is often followed by reference to Nazis.

Are recessive disease carrier screening, BRCA mutation testing, and NIPT eugenic, according to the definition? Only one might be, and even that’s questionable. Let’s dismiss the other two first.

BRCA testing alerts relatives to the need for active surveillance for certain cancers, for their own health. At least in my experience in counseling patients, an inherited cancer susceptibility is not a reason to keep one person from having kids with another, or to end a pregnancy, because the cancers are late-onset and treatable. Plus, a person who inherits a BRCA mutation must then undergo a second, somatic mutation in a cell in the organ that develops cancer, according to the classic two-hit mechanism. It isn’t the cancer that’s inherited, but the increased risk.

NIPT is not eugenic in its current guise because trisomies – extra chromosomes – result from mispairing in meiosis. They’re not inherited, they just happen, although a person with a trisomy is more likely to produce “unbalanced gametes” that can perpetuate the situation. But most new trisomies are spontaneous glitches that result from a chromosome pair not parting when it should as sperm or egg form.

The one type of testing that could ultimately have a eugenic effect is carrier screening for recessive diseases. The Counsyl paper concludes that “sequencing the entire genome of each patient would reveal ~10 times as many lethal recessives on average.”

Imagine including one’s personal collection of recessive mutations on a DNA dating site! (See yours truly quoted in The New Science of Matchmaking: Dating Based on Your DNA).

Natera’s description of the Horizon Carrier Screen leads potential patients through Mendel’s first law: an offspring of two carriers of the same condition faces a 25% chance of inheriting the disease. “If you find you are at risk, you can take steps to prevent having a baby with a genetic disease,” the clear explanation continues.

For couples who discover they carry mutations in the same gene, the company offers Spectrum, which uses pre-implantation genetic diagnosis (PGD) to choose embryos conceived in vitro that have not inherited the disease-associated genotype. PGD has been around since 1990, but occasionally headlines trumpet it as new.

So yes, filtering out mutations with rigorous and actionable carrier tests can ultimately alter the gene pool. And because the selection is directional, this appears to be eugenic by  permitting only certain gene variants into the next generation. But this isn’t really eugenics, because the important descriptor of eugenics is INTENT; that of medical genetic screening and testing is CHOICE. The goal of the first is sociological, the second, biological.

Genetic screening and testing often aim to avoid a medical situation in a family, not to “improve” the genetic structure of a future population. And we should never assume that all families will choose that path. I’ve talked to families that have more than one child with spinal muscular atrophy, or with a blood disorder, because preventing the birth of another affected child may seem a rejection of the beloved existing one. (See the DNA Science posts about the Amish for more examples.) Families must be allowed that choice. That’s what genetic counseling is all about.

And so I don’t think that any medical genetic screening or testing is eugenic, and I welcome the coming expansion of the opportunity to learn what’s in some of our DNA to more people.

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Black Pee Disease Offers New View of Arthritic Joints

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AlkaptonuriaA new cause of osteoarthritis identified by research on a rare disease,” ran the headline of a news release a few weeks ago. I was drawn to “rare disease,” even though I actually have osteoarthritis. When I read “alkaptonuria,” I was catapulted back more than a century to the first description of an “inborn error of metabolism.” The release announced a paper in the October Journal of Anatomy, which is behind a paywall.

So oft-told in the genetics lore is the story of understanding alkaptonuria that any geneticist would have recognized the reference instantly, as would most science writers. But the “aggregators” of science news? Not so much.

Google the headline and the parroting appears, oddly enough some of the echoes atop the original news release. One version invented a spin to up the excitement: “Scientists hoped to find out information on a rare disease. What they found instead was a potential cause of osteoarthritis,” with the subhead “An Accidental Discovery.” Please, give the researchers some credit for knowing to look at alkaptonuria as a model for osteoarthritis.

Joints commonly affected in osteoarthritis.

Joints commonly affected in osteoarthritis.

Investigating a rare disorder for insight about a common one is a classic strategy, not simply good luck. Statin drugs, for example, grew out of research on the one-in-a-million children who die young of heart attacks and strokes due to familial hypercholesterolemia (FH). Several DNA Science posts deal with a drug for the rapid-aging disease progeria that may also help those with conventional atherosclerosis.

THE FATHER OF INBORN ERRORS
Alkaptonuria is not quite as rare as FH, but is much more so than osteoarthritis. Alkaptonuria affects 1 in 250,000; osteoarthritis affects 13.9% of those over age 25 and 33.6% of people over age 65. Clinicaltrials.gov lists 5 studies for alkaptonuria (all for the same drug already used for a similar condition), and more than 2,000 for osteoarthritis.

Sir Archibald Garrod

Sir Archibald Garrod

To introduce “inborn errors of metabolism” in my human genetics textbook (new edition out soon!) I tell the tale of Sir Archibald Garrod and alkaptonuria. In earlier editions I wrote that the first sign is “urine that turns black upon standing,” which unfortunately caused legions of college students to think that people with the disease should sit down when they pee. This is why we authors need editors. The urine must stand, not the urinator (see photo above).

Sir Garrod (1857-1936) was a physician at St. Bartholomew’s in London when he investigated the odd disease at the turn of the twentieth century. The initial report in The Lancet in 1902 described the telltale excretion of homogentisic acid in urine that turned black upon standing. Sir Garrod focused on the observation that when one child had black urine, a sibling sometimes did too; 19 of 32 cases were from only 7 families. Plus, parents of affected children were more often first cousins than expected for such a rare condition.

Sir Garrod termed alkaptonuria an “alternative mode of metabolism,” realizing that people vary. He entitled that 1902 paper “The incidence of alkaptonuria: a study in chemical individuality.” It is that individuality that today’s exome and genome sequencing, not to mention genome-wide association studies, seek to reveal at the DNA level.

The phrase “inborn error of metabolism” didn’t appear until Sir Garrod’s Croonian Lectures to the Royal College of Physicians, published in 1909. That paper introduced “Garrod’s tetrad” of alkaptonuria, cystinuria, pentosuria, and albinism, defining an entire class of inherited illnesses.

Timing is critical in the story. Back in 1902, Mendel’s laws had just been rediscovered. That’s why much of  classic Lancet paper addresses whether the preponderance of cousin-cousin parental pairings and familial clustering revealed the recessive inheritance that Mendel had described so elegantly for peas.

Sir Garrod was astonishingly ahead of his time, zeroing in on the “one-gene_one-enzyme“ hypothesis that’s usually attributed to studies in bread mold circa 1941. The enzyme behind alkaptonuria wouldn’t be discovered until 1958, the gene in 1996. In today’s world of massive sequencing projects, I’m still stunned by the insights of long-ago researchers who deduced patterns of inheritance from what they could observe.

Homogentisic acid

Homogentisic acid

DARKENED CARTILAGE
In a nutshell, an inborn error blocks synthesis of an enzyme that is part of a metabolic pathway. Like a garden hose with a kink, stuff before the block builds up, and the stuff after is a dribble, or nothing.

In alkaptonuria, the deficient enzyme is homogentisic acid 1,2-dioxygenase, and the stuff that builds up, homogentisic acid, forms the greenish-black alkapton when exposed to oxygen (when a urine stream hits the air, or a splayed diaper).

431px-StateLibQld_1_49792_Advertisement_for_Dunlop_garden_hosesTyrosine is one of the 20 amino acids of life. Five stepwise reactions break it down, ultimately providing starting materials for production of thyroid and other hormones, the pigment melanin, and entrants to the energy pathways. Block a step, and a specific inborn error results. Alkaptonuria intervenes between steps two and three; blocks at the other points cause tyrosinemia. All hamper utilization of dietary proteins.

Darkened vertebral disc in alkaptonuria

Darkened vertebral disc in alkaptonuria

Early in life, alkaptonuria is mostly a peculiarity. The pigmentation – called ochronosis – typically doesn’t affect health until after age 30, when it darkens and degrades cartilage. The tips of the ears may blacken. Treatment is painkillers and joint replacement surgery to allieve painful arthritis. But alkaptonuria also causes kidney stones, heart valve damage, tendon and muscle rupture, and fractures.

ENTER HORSES
The arthritis of alkaptonuria is like that of the more common osteoarthritis, but is even more like a “novel pathology” of racehorses described by Alan Boyde, a professor of mineralized tissue biology (and a PhD and dentist) at the Barts and the London School of Medicine and Dentistry, in 2011.

Dr. Boyde and his group dissected digits of euthanized racehorses, and probed them non-invasively with “nanoindentation” and a slew of imaging techniques. They found “high density mineralized protrusions” – HDMPs. Hard spikes filling joint spaces. Ouch.

The key term is “non-invasively,” because it turns out that the reason these painful spikes haven’t been seen in those of us with run-of-the-mill osteoarthritis is that the technique to study joints destroys them! (See Heisenberg uncertainty principle: don’t alter what you’re trying to study!)

When Dr. Boyde and colleague Jim Gallagher, PhD, from the University of Liverpool’s Institute of Ageing and Chronic Disease and co-workers replaced a hip joint in a 49-year-old man with alkaptonuria, they decided to take a closer, less-destructive look. So instead of dissolving away hard stuff in the joint so they could see better, the researchers used a microtome to gently slice the tissue, like roast beef at a deli.

They saw HDMPs.

Spikes in a hip joint (University of Liverpool)

Spikes in a hip joint (University of Liverpool)

The researchers elaborate in the paper in The Journal of Anatomy that “despite extensive investigation, there is still a lack of knowledge of the microanatomical changes that ensue in osteoarthritis and their relationship to clinical symptoms. In part, this is because most histopathological studies of arthroses in humans have relied on thin sections of decalcified tissue, in which all evidence of mineral distribution in bone and calcified cartilage is destroyed.”

When the researchers went back to MRIs of the man’s hip, the telltale HDMPs were indeed there – but had gone unnoticed.

Gray340LOOKING AT COMMON OSTEOARTHRITIS
The next step was to look at joints from patients with osteoarthritis, which the investigators did for hip joints from two replacements and six cadavers. Keeping the joints intact again revealed the spikes of calcification. “We found several instances, enough to assure us that the research field should now be on the lookout for them,” the investigators write.

The spikes tend to appear near dead cells. Summed up Dr. Gallagher, “These small, sharp particles could act like an abrasive powder scouring the surfaces of the joint.”

Interestingly, the man with alkaptonuria had complained of severe joint pain, yet conventional X-rays had not shown advanced joint destruction. This reminds me of my husband’s frustrating visit to an orthopedist who informed him that he was imagining his severe back pain because the tools at the doc’s disposal hadn’t shown anything abnormal.

My own osteoarthritis appeared at age 33, as it did in my mother and her mother. Fortunately it only affects my hands, which I discovered upon whacking one of them and suffering surprisingly intense and long-lived pain, at about the same time that I became unable to play an F chord on guitar or form a fist. It’s in my neck and toes, but doesn’t really bother me much.

Random lessons learned from the alkaptonuria/osteoarthritis story:

  • Studying rare diseases in people and animal models (like racehorses) can unveil pathological mechanisms behind more-common, less-severe, counterparts.
  • If a physician claims a condition doesn’t exist, find a practitioner who will look at the problem another way.
  • In medical genetics, old stories are still valuable. It’s not all about genomics.
  • News aggregators and “content providers” who repeat repeat repeat verbatim and work for very little money are killing jobs for science writers, who have the experience to recognize the significance and backstory of news — and so much of science news these days reflects poorly-done studies (a 7-kid autism study on the nightly news?) or isn’t really news at all.
  • A frequent complaint about new editions of textbooks, such as the human anatomy and physiology textbooks I co-author, is that facts don’t change enough to warrant revision, that we know all there is to know about the human body. Not true.
  • The good news for human runners from horses is that development of joint spikes was not significantly associated with number of racing seasons, age, earnings, number of days in training, total distance galloped in one’s career, or presence of wear lines.
  • It’s ok to stand while peeing, even if you have alkaptonuria.

 

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Medical Success Stories: From Cystic Fibrosis to Diabetes

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dnaA skinny little boy, with mocha skin and curly black hair, lived in the apartment building next door when I was growing up in Brooklyn in the 1960s. I don’t remember his name, but I recall that he didn’t live long enough to go to kindergarten. He had cystic fibrosis.

Today’s tots with CF face a far brighter future. A recent report in the Annals of Internal Medicine applied trends in survival from 2000 to 2010 to project life expectancy for children diagnosed in 2010: 37 years for girls and 40 years for boys. (The difference may reflect hormones or the extra creatinine in the more muscular male of the species.) Factoring in the current rate of treatment improvements gives a soaring median survival of 54 years for women and 58 years for men when those kids grow up!

This is spectacular news, although some younger people with severe disease will still contribute to the lower end of the survival curve. (See my write-up in Medscape and a recent post here on the history of CF.)

Cystic fibrosis results from an absent or malformed chloride channel.

Cystic fibrosis results from an absent or malformed chloride channel.

THE CFF PATIENT REGISTRY
The Cystic Fibrosis Foundation Patient Registry began in 1966, about when my young neighbor died. It has followed 26,000 of the nearly 35,000 individuals with CF in the U.S., with 5,000 added over the past decade as treatments have expanded and people with milder symptoms added.

In the early days, deaths were more often due to malnutrition than to the impaired respiration for which the disease is best known.

Success has come from diverse realms.

First came high-calorie diets, digestive enzymes mixed into applesauce, and airway clearance exercises, eventually helped with devices such as vibrating vests. Then came a parade of drugs: antibiotics, mucolytics, and more recently Kalydeco to refold misfolded CFTR (CF transmembrane conductance regulator) protein, a drug so effective that it’s Facebook page is called Kalydeco Miracles. And treatments start sooner in life thanks to universal newborn screening (since 2009) and prenatal carrier testing.

IS CF MORE THAN ONE DISEASE?
The definition of CF continues to evolve as more mutation combinations are identified and their phenotypes described. It has never made sense to me that different mutations in the CFTR gene all produce what we call cystic fibrosis, yet different mutations in the

Hemoglobin

Hemoglobin

beta globin gene cause different clinical entities. Hemoglobin C and sickle cell disease even affect the same amino acid position. The situation in naming single-gene diseases seems a little like how lumpers and splitters see biological classification.

But that may be changing. A recent report in PLOS Genetics suggests that CF is two diseases, defined by whether or not the lungs are affected. At least nine variants of CFTR spare the lungs, but cause male infertility, pancreatitis, or sinusitis — in some men, all three.

“Pancreas cells use CFTR to secrete bicarbonate to neutralize gastric acids. When that doesn’t happen, the acids cause the inflammation, cyst formation and scarring of severe pancreatitis. Bicarbonate transport is critical to thin mucus in the sinuses and for proper sperm function,” explains co-author David C. Whitcomb, MD, PhD and chief of gastroenterology, hepatology and nutrition at the University of Pittsburgh School of Medicine. In times past, CF wasn’t part of the differential diagnosis for men with pancreatitis, chronic sinusitis and infertility, but with working lungs.

CF affects more than the respiratory system.

CF affects more than the respiratory system.

“I know one MD who got through med school a severe asthmatic, now diagnosed with CF. We are diagnosing people better at all ages, and newborns are being screened, which contribute to increase in life expectancy,” says Paul Quinton, PhD, a professor of biomedical sciences at the University of California, Riverside, School of Medicine and medical advisor to Cystic Fibrosis Research Inc.. He has CF.

Dystrophin

Dystrophin

Tracking the natural history of a disease, which patient registries makes possible, is crucial in determining whether a new treatment works. For example, a recent DNA Science post asked whether boys with Duchenne muscular dystrophy who walked farther on a treadmill in a set time after receiving an experimental genetic treatment had really improved, or if their strides were within the range of normal for the disease.

Natural history studies reveal aspects of disease that could be important in developing treatments. For CF, the registry revealed a period of increased risk during adolescence. Until age 10, annual mortality is below 0.5%, but it jumps during the teen years to 3-4% before plateauing at age 25.

An editorial accompanying the Annals of Internal Medicine paper suggests suggests that the tendency of teens to not eat so well and forego treatments and therapies, and increased susceptibility to pathogens such as Pseudomonas aeruginosa and MRSA, might explain the vulnerability.

SURVIVORS OF CHILDHOOD DISEASES
How will the health care system embrace a population of adults with CF?
While the editorialists claim “caring for adults with CF requires a village,” Lisa Tuchman MD, MPH, an adolescent medicine specialist at Children’s National Medical Center, is more positive. “We‘re seeing a trend across all pediatric-onset health conditions. For CF there has been a lot of thoughtful planning and careful analysis, mostly facilitated by the registry.” Dr. Tuchman and Michael Schwartz, MD, from the Pediatric Pulmonary Medicine & Cystic Fibrosis Center, Lehigh Valley Health Network, recently published a study in Pediatrics about successful transition to adult care for people with CF.

I asked Dr. Tuchman whether there are precedents for extended-survival patient populations. “Lots! Over 90% of little kids who get cancer are going to survive, so the system has responded by creating centers for adult survivors of childhood cancers. We see this in sickle cell disease, adult programs because people are living longer with it. And a lot of babies born with HIV disease are now young adults transferred to adult health care systems. It is across the board: metabolic diseases, hemophilia, diabetes. There’s a growing population of adults with pediatric-onset conditions,” she said.

GENE THERAPY
A brute-force attack on symptoms, coupled with a targeted molecular approach, has tamed cystic fibrosis. Although news reports describe Kalydeco as correcting CF at its source, to my geneticist mind, the source of inherited disease is not the protein, but the gene that encodes it. And that’s where gene therapy comes in. It, too, has had recent spectacular successes.

Corey Haas would likely have been blind by now, if not for gene therapy.

Corey Haas would likely have been blind by now, if not for gene therapy.

One of my books chronicles development of gene therapy for Leber congenital amaurosis type 2, which has given vision to more than 200 people, many of them children. Other blinding conditions aren’t far behind.

At the American Society of Gene and Cell Therapy annual meeting last May, I heard similar stories, most notably for adenosine deaminase deficiency and severe combined immune deficiency (SCID) X1. Said Adrian Thrasher, MD, PhD, from Great Ormond Street Hospital for Children of ADA deficiency, “We expect to cure a majority of these kids today if they can have a bone marrow transplant, but if they can’t …” and he then launched into the details of ongoing clinical trials for gene therapy. It works, saving children who would otherwise die in infancy from infection. ADA deficiency, like CF, is no longer a “life-shortening inherited disease.”

And the list will grow, especially as “traditional” gene therapy of supplying working genes shares successes with genome editing techniques that actually replace or fix faulty genes.

Heather Lewis. Gastric bypass surgery banished type 2 diabetes.

Heather Lewis. Gastric bypass surgery banished type 2 diabetes.

GASTRIC BYPASS AND DIABETES
Although I know double-blinded, controlled clinical trials are the best way to demonstrate efficacy of a new treatment, the most compelling example for me was watching my daughter Heather following her gastric bypass surgery last May.

Her type 2 diabetes vanished, in just 4 days.

I’d read the reports of gastric bypass surgery curing diabetes. And Heather’s physician had told me that more than 90% of the bypass patients with diabetes at Albany Medical Center no longer had the disease. The hypothesized mechanisms make sense: dampened secretion of ghrelin, the stomach’s hunger hormone; or forcing glucose out of the bloodstream into the rerouted small intestine to provide energy to digest food that’s a bit chunkier than normal.

Heather’s surgery had been delayed two months because she couldn’t get her A1C down – the 3-month measure of blood glucose. She went from one to two to three oral diabetes drugs, with exercise and a very low carb diet. I even invented a low glycemic index soup/stew that helped a little. But only insulin worked. Looking ahead to a lifetime of treating diabetes is what pushed Heather to have the surgery.

Someday, gastric bypass surgery could be a front-line treatment for type 2 diabetes, even among people of normal weight. In terms of both economics and quality of life, it makes sense. Or perhaps we’ll find a way to less-invasively recreate the altered microbiome of a person after weight loss surgery who no longer has diabetes.

Double Helix with StethoscopeLet’s hope that cystic fibrosis, Leber congenital amaurosis, and type 2 diabetes are only the beginning of a trend towards tackling disease, in a multitude of ways.

(Update: Eman in Liberia from my last post remains healthy, and is trying to volunteer with MSF until med school restarts. And I’m recovering from major surgery, so may miss a week of posting here and there.)

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Update: How Ebola Kills

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Eman Gokpolu (with Larry) is my African "son." He sends frequent updates from Liberia.

Eman Gokpolu (with little Larry, named for my husband) is our African “son.” He sends frequent updates from Liberia.

Eman’s emails arrive hours ahead of the news here. He wrote on Sunday, August 17:

“An Ebola quarantine site was  attacked and looted. News is that most of the patients have escaped. This is going to put more fear into the population. All this because people are denying the virus.  More people might get exposed.  I’m so weak I can’t wake up this morning. Its 6:00 pm and I am still in bed listening to the news.  All this happened in a very populated area called West Point. Got pain all over my body. Keep me in your meditations.”

As a medical student Eman can't treat people, so he is a  "sensitizer," educating people on how to avoid infection.

As a medical student Eman can’t treat people. Instead, he is a “sensitizer,” educating people on how to avoid infection.

Emmanuel is a medical student in Liberia whom my husband and I have been supporting since he contacted me after reading my human genetics textbook in 2007. Until the fever hit him last weekend, he dedicated himself to “sensitization,” educating the public about how to stay safe. But now he’s too sick and weak to venture out.

His email from Monday, August 18, said only “Need help!

Eman is our son in the African sense, not based on his DNA. And our families have grown close. Some of the funds we sent to see him through medical school helped put his mother through nursing school. It costs a fraction of medical education here.

The emails and texts from Liberia are eerie in the face of the crumbling infrastructure, the abandoned hospitals and schools. Eman taps on a phone these days, too terrified to use an Internet cafe as he has in the past. We know he’s in trouble when his brother Joseph takes over — it means Eman is in the hospital. It’s happened for cholera, amoebiasis, and cerebral malaria more than once. Fighting infection is a way of life in Liberia.

I’m mortified when the news here focuses on the deaths of individuals — tragic as they may be — while the populations of African nations like Liberia, of the entire continent, are under threat. Eman wants to know why the US didn’t pay attention until the arrival here of two patients, who were treated. So do I.

JUST 7 GENES

The stark seeming-simplicity of the Ebola virus flashes across my mind whenever I receive an email from Eman.

Ebola virus has a mere 7 protein-encoding genes, but the RNA that is its genetic material holds hidden information. One key gene (GP, for glycoprotein) has an overlapping reading frame so that an alternate form harbors a stretch of added adenines. And the encoded protein is cut after translation, generating a mature secreted form that sits on the surfaces of viral particles, as well as a sugar-coated smaller part, like a moon carved from a planet.

(Wikimedia Commons)

(Wikimedia Commons)

The irony of it all is stunning. Genetics and genomics journals overflow with data. Always more exomes, more genomes, meta-analyses of meta-analyses that search for meaning among the nearly limitless combinations of variants of our 20,000 or so genes. And yet a 7-gene “infectious particle,” so streamlined it isn’t even a cell, isn’t even alive, can reduce a human body to a puddle, inner barriers dissolving into nothingness, within days.

How does Ebola virus, so much simpler than influenza, than HIV, do it?

AN EBOLA TIMELINE
Ebola virus homes to certain immune system cells as well as the boxy epithelial cells that aggregate into layers and the single bathroom-tile-like endothelial cells. Inside the body, the virus first tackles innate immunity – the immediate and generalized response to infection. Ebola commandeers monocytes and macrophages, the wandering cells that travel around the body, dividing, distributing its deadly cargo.

Meanwhile, the virus replicates like crazy.

(Wikimedia Commons)

(Wikimedia Commons)

In those who will not survive, the innate immune response goes on a tad too long. The virus also invades dendritic cells. These are the sentries that “present” the pathogen’s provoking antigens to the parts of the immune system that carry out the second phase, the slower and targeted adaptive response. And indirectly, mysteriously, lymphocytes die en masse, instead of producing antibodies.

Yet at the same time, a “cytokine storm” erupts, sending other arms of the immune response into overdrive. Levels of gamma interferon, interleukins 2 and 10, and tumor necrosis factor soar, triggering fever and flu-like symptoms. Yet it’s as if there’s no interferon at all. Viruses do not see it.

The bizarre immune response during Ebola infection is rightfully termed “paradoxical,” at once too slow, too little, too intense.

Then the body’s barriers begin to break down.

The endothelial cells that curl into the tiny tubes that are the capillaries, and also line the interiors of larger blood vessels, contort into blobs. Holes appear. Barriers melt away, and the fluids that they contained redistribute. The still-crazily-replicating virus now has direct access to organs, favoring the adrenal cortex (plunging blood pressure), the kidneys, gonads, spleen, and most dangerous, the liver.

(Wikimedia)

(Wikimedia)

The final stage is the bleeding, as the liver’s output of clotting factors becomes unhinged. One protein in particular goes by various names: in the older literature it’s simply “tissue factor,” but is also known as thromboplastin, CD142, and factor III.

Whatever it’s called, this cell surface glycoprotein converts prothrombin into thrombin, the essential final step in blood clotting. The fact that no deficiency of thromboplastin is known – the others cause hemophilias and other clotting disorders – belies its importance.

In Ebola infection, thromboplastin is too active, ushering in disseminated intravascular coagulation. Tiny clots form in blood vessels everywhere. Organ necrosis sets in as the blood supply ebbs, and clotting factors needed to stanch greater breaches as the blood vessels come apart become depleted. Hemorrhaging begins as the biochemical balance so critical to appropriate clotting vanishes.

Nicotiana benthamiana, the tobacco plant in which ZMapp is made. Thanks, GMOs!

Nicotiana benthamiana, the tobacco plant in which ZMapp is made. Thanks, GMOs!

BACK TO THE GENES
A human body overwhelmed with Ebola virus is like a castle whose defenses fail, from the inside out, all orchestrated by that puzzling handful of genes.

GP targets the virus to certain cell types, deforms the endothelium, and destroys antigen presentation. ZMapp, the drug being given to a handful of infected people ahead of human testing because it worked in macaques, counters GP. It consists of three monoclonal antibodies produced in tobacco cells.

Gamma interferon

Gamma interferon

VP24 cuts off the host transcription factor STAT1, which is required to use gamma interferon, according to a recent report in Cell Host & Microbe. And VP40 protein, because it forms the outside of the virus, should elicit an antibody response, only it usually doesn’t.

The power of a virus such as Ebola tends to evoke anthropomorphism. But the virus isn’t intentionally trying to kill people, as one prominent researcher told the New York Times, calling the virus “a survivor. It does what it can to avoid the human immune system.” It doesn’t think.

Another type of survivor might provide the clues necessary to stop the current epidemic: people whose immune systems can fight off the virus.

LEARNING FROM SURVIVORS
Just as HIV antivirals were developed using clues from people who never became infected despite repeated exposure, a solution to Ebola hemorrhagic fever might lie among individuals who recover.

Survivors have 10 million viruses per milliliter of blood serum; people who succumb have 10 billion. So far we know that the immune response in people who survive is subtly distinctive, the innate response turning off at a specific point and the adaptive response beginning in time to help, neither becoming overactive. Identifying biomarkers may reveal the specifics that drive resistance, such as an adhesion factor that re-attaches torn endothelium.

eman gradEbola hemorrhagic fever is the consequence of runaway viral replication against a backdrop of a strangely deranged immune response. We know the viral genome sequence, and I’m sure the genome sequences of survivors are being or will soon be sequenced. I hope it is only a matter of time until researchers deduce how variations of the 20,000-gene human genome or its expression resist the 7-gene genome of Ebola virus, and figure out how to replicate the response.

Until they do, I’m petrified. I just got an email sent from Eman’s phone — from Joseph, August 20.

“Eman walked to the hospital today because according to him, he is not doing well. He called me up in pain. Luckily, its not Ebola. We were so scared. He’s admitted. No word yet. I will keep you informed. Joseph”

Update Sunday August 24: Eman is still in the hospital, but he “only” has hookworms and malaria (which he always seems to have). When he gets out tomorrow, he plans to volunteer with MSF to fight Ebola.

 

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ALS Target: Microglia

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deboer1HRGlia, perhaps the most underappreciated of cell types, are finally getting some attention. A new report in Science Translational Medicine from Kevin Eggan’s group at the Harvard Stem Cell Institute validates the role of microglia in amyotrophic lateral sclerosis – aka ALS, motor neuron disease or Lou Gehrig’s disease — and investigates how to manipulate them to extend life, in a mouse model for now.

NOT JUST BYSTANDERS
Often described as inert scaffolding, bystanders, or background cells, neuroglial cells – glia for short– actually do quite a lot. In the central nervous system, the several types -– astrocytes, oligodendrocytes, ependymal cells, and microglia — provide nutrients and growth factors, mop up excess neurotransmitters from synapses, form the intricate architecture that supports axons, provide insulating myelin, and control the communications of neurons.

The relative numbers of neurons and glia have long been a matter of debate, but consensus seems to be emerging of a near 1:1 ratio. And because neurons don’t divide and glia do, there’s a lot of life and death among the so-called bystanders. Not surprisingly, when brain tumors form, they’re typically glial. Neurons must revert to a more plastic developmental state to veer onto a pathway towards cancer.

When I began coauthoring a human anatomy and physiology textbook years ago, one of the first things I did was to redo the glia section, freeing them from their stereotyped supportive roles and giving them proper respect.

All specialized cells derive from pathways that branch from stem cells. Most glia are cousins of sorts to neurons, descending from division of the same neural progenitor cells. Yet some microglia come from hematopoietic stem cells, the “mother” cells of the bone marrow. Brain cells coming from the bone marrow makes it possible to treat some brain diseases with bone marrow transplant, such as adrenoleukodystrophy. Clinicaltrials.gov lists a few such efforts for ALS.

Microglia mediate signaling of prostanoids, which include the prostaglandins, hormone-like fatty acids that control inflammation, among other activities. In the brain microglia aggregate near damage, but in ALS, overactive versions of the cells might contribute to the pathology. PET scans show supercharged microglia in the brains of ALS patients, and heightened signaling in their spinal fluid.

Dr. Eggan and colleagues called attention to the possible role of microglia in ALS in 2008. “Now 6 years later, after considerable effort and many long-term experiments, we’ve been able to better pinpoint the source of those signals in the nervous system in an animal model, as well as show that the prediction we made using a stem cell model of disease can hold up to closer scrutiny in the context of a whole animal,” Dr. Eggan said in a news conference yesterday. The research trajectory is in a sense circuitous, demonstrating mechanisms in human cells that are then repeated in mice, to collect evidence to catalyze clinical trials of compounds that intervene in the pathological process.

STEM CELLS ARE CRITICAL FOR STUDYING NEURONS

Human motor neuron from iPS cells from ALS patient (Gist Croft + MacKenzie Weygandt)

Human motor neuron from iPS cells from ALS patient (Gist Croft + MacKenzie Weygandt)

Using human embryonic stem (hES) cells or induced pluripotent stem (iPS) cells is particularly important in studying diseases of the nervous system because neurons don’t divide. Otherwise where would new ones come from in a culture dish?

Contrary to the popular but deficient definition of stem cells as “cells that can turn into any cell type,” the defining characteristic is ability to self-renew – make another stem cell. If stem cells magically “turned into any cell type in the body,” there would quickly be nothing left to keep things going.

A stem cell can self-renew and generate a neural progenitor cell that in turn can divide to give rise to neurons and glia. The Eggan team first created iPS cells from an ALS patient  in 2008.

Microglia apparently harm motor neurons via a specific type of overactive prostanoid receptor. First author and grad student Sophie De Boer and her colleagues at HSCI, Massachusetts General Hospital, and Boston Children’s Hospital, conducted a brilliant series of experiments that show that blocking or removing the errant receptors may be one route to extending survival in ALS.

ELEGANT EXPERIMENTS

Human embryonic stem cells

Human embryonic stem cells

In the new study, the investigators exposed human motor neurons derived from ES cells and marked with green fluorescent protein (GFP) to sheets of “toxic” glia from mice that have a form of ALS due to mutation in the superoxide dismutase 1 (SOD1) gene. At last count, 7 human genes had been implicated in the 5 to 10% of cases that are inherited; SOD1 was the first and is the best studied.

The SOD1 toxic microglia killed more than half of the neurons, but chemically blocking the receptors enabled the neurons to survive.

In complementary experiments, activating receptors in normal glia turned them toxic – but only to motor neurons, and not other neuron types. Removing the gene encoding the protein that forms the receptor had the same effect as blocking it chemically. And perhaps most important in a translational medicine sense, a short blast of antagonist had a long-lasting effect on the health of the motor neurons. Plus the effect is seen in actual living animals, increasing lifespan in mice.

The most exciting part of the new work is that it zeroes in on a “druggable” target – the DP1 receptor and its associated signalling pathways. The receptor is a G protein, a membrane-spanning molecule that is already the basis of many drugs. Said Dr. Eggan, “At least two major pharmaceutical companies have significant development programs around this receptor for another indication — niacin induced flushing.” Perhaps these candidate drugs can be retasked to inhibit inflammatory effects in ALS, he added, and possibly teamed with a seizure medication the researchers identified earlier this year that fights ALS by a different route.

WHAT CAUSES ALS?
640px-2006_Pro_Bowl_tackleALS is like Alzheimer and Parkinson diseases in that a shared phenotype might represent any number of different gene-environment interactions. What’s true for an individual with SOD1 ALS may not be so for a person with a different mutant gene.

The ALS patient I posted about in April, Glenn, didn’t have any known mutations, but he did have a few environmental risk factors. He played football for many years, maybe getting clunked in the head one too many times, and may have been exposed to pesticides when his boyhood home (to which he moved back as an adult) bordered fields of crops. Smoking, aspartame, and exposure to formaldehyde and heavy metals are other suspects. Reports that vitamin E protects against ALS haven’t held up.

BMAA, an amino acid implicated in ALS that is not part of dietary protein.

BMAA, an amino acid implicated in ALS that is not part of dietary protein.

Perhaps the most fascinating causal candidate is exposure to cyanobacteria (aka blue-green algae) living in cycad trees on Guam. The cyanobacteria release an amino acid called BMAA into the soil, where it makes its way through the roots to the seeds of the cycads. After biomagnification through food webs, BMAA causes an ALS-like disease when it binds proteins in the brains of some individuals, who may be genetically-predisposed to the motor neuron damage.

STEM CELLS FIND THEIR NICHE

Do people survive ALS? The disease may be so heterogeneous that this might be possible. One commentator on my previous ALS post took me to task for not mentioning this idea, which I admit I was not aware of, but I found his tone disturbing. He wrote:

“C’mon, time to wake up and smell the coffee. People have been solving ALS for years, and the only way to really do it is change diet, psychology and lifestyle.”

He linked to a website offering accounts of recoveries, and then commented on Dr. Eggan’s team’s identification of the seizure drug for possible repurposing:

“While maybe that drug will be of some use somehow, don’t let that distract you from the overall reality of the situation. Stem cells? Eh, just learn to heal.”

There's more to finding a treatment for ALS than just "making it so."

There’s more to finding a treatment for ALS than just “making it so.”

I don’t think the commentator intended to upset ALS patients who haven’t managed to heal themselves, and I understand the value of hope. But an anti-science stance certainly isn’t going to help. I’m reminded of Captain Picard on Star Trek: Next Generation saying “make it so,” or the professor in The Music Man teaching kids to play instruments using the “think” system rather than learning music theory.

Positive thoughts aren’t enough.

Using stem cells to recapitulate the precise choreography of a disease, illuminating the various drug targets and their interactions, and then deploying drugs old and new based on those discoveries, may indeed “make it so,” slowing, vanquishing, and ultimately preventing this heartbreaking and complex disease.

I think that use of stem cells to create “diseases-in-a-dish” will turn out to be their most successful application. The very quality of self-renewal that many news reports omit is what scares me. Stem cells used therapeutically that self-renew, perhaps in places unexpected, could form a tumor.

Coincidentally, I just received an e-mail from Maurie Hill, whose participation in a clinical trial to treat Stargardt disease, a form of visual loss, was the subject of the very first DNA Science post, Human Embryonic Stem Cells Finally Reach Clinical Trials: Maurie’s Story, nearly two years ago. Alas, her vision has not improved at all, although I do not know the findings of the frequent tests she undergoes — just that she’s very disappointed.

But use of stem cells wedded to drug discovery? That’s a can’t-miss! Congrats Eggan lab for the continuing fine work.

 

 

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Gene Test Predicts Blindness After LASIK

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Granular_corneal_dystrophy_type_I._Numerous_irregular_shaped_discrete_crumb-like_corneal_opacitiesMillions of people have put aside their eyeglasses or contact lenses thanks to a procedure called LASIK. But for carriers of a rare condition called granular corneal dystrophy (GCD), LASIK can damage the cornea, even causing blindness. The Avellino DNA Dual Test for LASIK Safety, from Avellino Laboratory, can identify individuals genetically predisposed to this complication, offering a great example of an “actionable” genetic test.

Ophthalmologists can provide the cheek swab test to patients considering LASIK, and results are available within 2 days. Company founder and CEO Gene Lee pursued development of the test after learning about the genetic connection in early 2008. It’s now standard-of-care in Korea and Japan, and became available in the US in April. Insurance typically doesn’t cover it (yet), but the test is often incorporated into a work-up for LASIK, and out-of-pocket costs about $100.

“We started doing it last year and we’ve found it to give increased peace of mind and confidence in the procedure. If someone has this condition and it is clinically apparent and visible, the test would just confirm the visual findings. But a number of patients have subclinical findings or none, and this genetic test is the only way to identify the condition,” Richard Rothman, MD, an ophthalmologist who practices in Las Vegas told me. And patients who have the mutation can tell their relatives to be tested before choosing LASIK.

THE GENETICS OF GRANULAR CORNEAL DYSTROPHY

TGFBI

TGFBI

GCD results from mutations in the transforming growth factor beta induced (TGFΒI) gene, which encodes the protein keratoepithelin. The affected part of the cornea, the stroma, consists of extracellular matrix (the goo between cells) and stacks of collagen fibrils, with some other proteins such as fibronectin and integrins, and scant keratocytes that produce the keratoepithelin that keeps the cornea clear. Combine carrying a mutation with stress – such as radiation, hypoxia, chemotherapy, peroxide, or perhaps a laser procedure — and keratoepithelin misfolds into a gunky, amyloid-like mess.

The two types of GCD are due to mutations in different parts of the gene. The type 1 or classic presentation results from a mutation in exon 12, giving a “bread crumb” like appearance to the cornea. Type 2 is known as “Avellino” because the first identified cases, in 1988, lived in the town by that name in Italy. This type resembles a “snowflake icicle” due to a mutation in exon 4 (the exons are the parts of genes that encode protein). Other studies identified patients in Japan and Korea, and then pretty much everywhere.

For individuals who have two mutations (homozygotes), proteins deposit in the corneas during infancy, causing blindness by the teens. The condition is much milder, with later onset, in people with one mutation (heterozygotes). But if vision isn’t very impaired, or begins late in life, then visual loss rather than improvement months to years after LASIK comes as quite a shock. People can carry the mutation and not know it. And that’s where the test comes in.

A DISORDER OF PROTEIN MISFOLDING

LASIK

LASIK

LASIK (laser-assisted in situ keratomileusis) creates a thin flap in the cornea that is hinged back to reveal the middle layer, where an excimer laser is applied to alter the topography to better focus light rays on the retina. Normally, the intervention activates transforming growth factor beta to repair the wound. But in people with one mutation, the surgery makes keratoepithelin misfold and aggregate at the flap. This action accelerates the corneal dystrophy and may cause another complication in which torn collagen fibers bind various proteins, producing a “sands of Sahara“ effect. Ouch.

Avellino DNA Dual TestGCD is rare. Avellino Laboratory has identified 390 people with one or two mutations among 420,000 being worked up for possible LASIK. More than 30 mutations are known, and they also account for the related condition lattice corneal dystrophy. The nomenclature is still traditionally clinical, based on appearance, but subtyping now reflects genetic distinctions. For families aware of the pattern of inheritance because homozygotes are blind, full gene sequencing is available from several labs.

LET’S NOT FORGET SINGLE GENE TESTS
Every morning, I look through digests of news releases about genetic research from a wonderful service from the American Association for the Advancement of Science called EurekAlert. A few weeks ago, the news release about the LASIK genetic test caught my eye because of its simplicity, its utility, and the fact that it looks for mutations in ONE gene. That’s unusual these days.

(Dept. of Energy)

(Dept. of Energy)

More often, the studies in the news release roster, and therefore those that make the news, deal with big data. They track thousands upon thousands of sites in genomes that vary among individuals, boiling down to a dozen or so that can serve as usually weak risk factors (genome-wide association studies or GWAS); follow epigenetics (sites of methylation) and changes in gene expression; or sequence exomes and genomes. All good of course, but usually not immediately of any help to patients. And many news releases mix up the techniques or write so vaguely that it’s difficult to know what exactly the findings are without reading the technical papers.

Around the time of the LASIK news release was another on a GWAS finding a dozen risk sites for Parkinson’s disease, a report in the Journal of Urology tracking methylation profiles of three genes that predict which prostate cancer biopsies are false negatives, and reports on finding common gene variants behind autism and schizophrenia. Inheriting a mix of variants can set the stage for each condition. An additional, triggering mutation or exposure to an environmental factor might then turn risk into reality.

These are all quite different genetic scenarios than a single gene mutation that makes itself known after surgery injures the eye.

I realize that large-scale investigations take massive and talented teamwork, and that the projects are vital to understanding pathology, which fuels new treatments. But I’m starting to feel an information overload that makes me appreciate the single-gene tests that a patient can benefit from right now. Many have been available for years, but we don’t hear about them as often as the megadata. They’re not news.

Blausen_0290_DeepVeinThrombosisPerhaps the best example of a an actionable single-gene test is the one for factor V Leiden, a mutation in a clotting factor gene. Knowing it’s there means you can avoid dangerous clots by taking blood thinners, wearing special support socks, and avoiding long plane rides or crouching for long periods, as reporter David Bloom did in 2003 when reporting from Iraq in a tank with his legs folded underneath him for hours. He died of a pulmonary embolism following deep vein thrombosis.

I hope that single-gene test panels, such as those for cardiovascular disease or Jewish genetic diseases, don’t become completely buried by the avalanche of genomic megadata.

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Vaccine Memories: From Polio to Autism

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Salk_Thank_You“April 15 – Polio Vaccine Perfected!!!!”

So wrote my mother in 1955, on the “Baby’s Health Record” page of my baby book. I unearthed it a few days ago while looking for some old writing clips.

Just a day earlier, I’d just reported in Medscape on a study finding that adding injected Salk polio vaccine to the oral Sabin vaccine series can boost immunity in parts of the world where polio is still endemic, such as Nigeria, Pakistan, and Afghanistan.

The coincidences continued.

THE SUMMERTIME NIGHTMARE OF POLIO

Herd immunity protects a population against an infectious disease when enough individuals are vaccinated to block spread of the pathogen.

Herd immunity protects a population against an infectious disease when enough individuals are vaccinated to block spread of the pathogen.

Among my old article clips I soon found “Polio Eradication  Goal Extended,” in The Scientist from 2000, which had been the target year for ending polio. I’d quoted U.S. Secretary of Health and Human Services Donna Shalala defining herd immunity on a global scale: “No nation is truly free from polio unless every nation is free of polio.”

It’s a message that needs repeating, for a number of infectious diseases.

My Scientist article began with a glimpse of the pre-polio-vaccine days:

An iron lung took over for the flaccid chest muscles of people with polio.

An iron lung took over for the flaccid chest muscles of people with polio.

For parents of young children in the early 1950s, summertime brought the terror of a fever that might explode into ‘infantile paralysis,’ a fear propelled by images of Franklin D. Roosevelt’s battle with the disease. Although only 1 percent of infected individuals developed severe symptoms as the virus invaded spinal cord cells, the number of cases grew large enough to inspire a massive effort to develop a vaccine, including the founding of the March of Dimes in 1938 to specifically battle polio.

For those old enough to remember the Beatles, polio vaccines were part of childhood. By 1955, youngsters in many nations received injections of Jonas Salk’s inactivated polio vaccine. By 1962, children were lining up at school, tongues out to receive pink-stained lumps of sugar impregnated with Albert Sabin’s live, attenuated oral polio vaccine.”

Neither Salk nor Sabin sought patent protection for their inventions, which offer the best protection when teamed. The first vaccine, live but weakened, was actually invented in 1948 by virologist Hilary Koprowski, director of the Wistar Institute in Philadelphia for 30 years. He died last year.

Kathleen Sebelius gives oral polio vaccine to a child in India.

Kathleen Sebelius gives oral polio vaccine to a child in India.

Sabin’s oral vaccine, much more acceptable to the kindergarten set than a shot in the arm, sent attenuated virus directly into the gastrointestinal tract. To develop the oral vaccine, passage through several non-human animal hosts weakened the virus so that it activated immunity in people without causing disease.

Stool from kids who ate the sugar cubes released the weakened poliovirus into sewage, spreading protection even to those who hadn’t been vaccinated, like older people. But the virus can mutate, as live viruses do, sometimes into a form that invades nerve cells. Very very rarely, this causes the acute flaccid paralysis of poliomyelitis.

baby bookTHE “CHILDHOOD DISEASES”
My sister Edith had the good sense to be born after me, and even though that meant she was a mere penciled-in footnote in my baby book, she had some vaccines for which I suffered through the associated illnesses. We straddled that time when the classic illnesses of childhood began to go away.

When I was 3 I had the measles for a full month. During a house call, the pediatrician prepared my parents for the chance that I might need to be hospitalized, and possibly lose my hearing or end up brain damaged. Fortunately I recovered.

A few years later I watched several people hold down a screaming Edith as she got the new measles vaccine, 2 shots back then. But we both had mumps, chickenpox, and German measles, their vaccines not yet perfected. She reports recalling her delight at expecting a shot and getting a sugar cube.

Because smallpox vaccine was initially derived from cowpox lesions, people feared the vaccine would cause tiny bovines to emerge from the skin. This famous cartoon is from 1802.

Because smallpox vaccine was initially derived from cowpox lesions, people feared the vaccine would cause tiny bovines to emerge from the skin. This famous cartoon is from 1802.

According to my baby book, my smallpox vaccine of April 5, 1955, didn’t take, so I had it again on May 6. Now we don’t hear much about smallpox unless it’s discovered in a back room at a government lab.

May 6, 1955 must have been a bad day for me (and my mother), because I had my first whooping cough (pertussis) vaccine then too, and again a month later. Edith had to have pertussis vaccine again just last week because she’s visiting her about–to-be-born first grandchild in California, where the disease has returned due both to natural waning of the immune response and to people who won’t vaccinate their children. Pertussis can kill a baby.

During my first year I also had 4 diphtheria shots and 1 for tetanus, the DPT vaccine, now called Tdap, yet to have been combined into existence. It is the main target of the anti-vaccine movement.

Thanks, mom, for getting me vaccinated.

Thanks, mom, for getting me vaccinated.

I had my polio vaccine shots in May, June, and October of 1956. Being a toddler, I didn’t know that the vaccine had run into trouble right out of the gate. Thirteen days after its debut in April 1955, the product from Cutter Labs in Berkeley, California, was found to harbor live virus, which infected 94 vaccinated kids and 166 of their close contacts. On May 7, the Surgeon General suspended the polio vaccine program, spearheading government vaccine surveillance. Polio vaccinations resumed in the fall of 1955, much to the relief of millions of parents.

My mother, back in 1955, understood the concept of herd immunity, if not by that name. Grateful and relieved parents throughout the U.S. realized that if enough people were vaccinated, active virus would have nowhere to infect, and polio would go away.

An alternate possible explanation for the rise in autism cases: extended use of folic acid in pregnancy.

An alternate possible explanation for the rise in autism cases: extended use of folic acid in pregnancy.

AUTISM AND FOLIC ACID
I hated vaccines because they hurt, but even as a small child wondered how they worked. And because some of my earliest memories are of those first vaccines, I signed on as this year’s keynote speaker for the  March of Dimes student convocation when I learned that the first speaker, in 1971, was Jonas Salk.

At the last talk in the series, at the Institute for Basic Research in Staten Island, Mohammed Junaid, PhD, head of the structural neurobiology lab there, talked to the high school students just before I did. His team’s data may explain the increase in incidence of autism: folic acid supplementation extending well beyond day 28 of gestation, when it prevents neural tube defects (NTDs). So far they’ve got an association (timing) and a possible mechanism (epigenetics). The vaccine connection, of course, is the blame for the uptick in autism cases.

Folic acid

Folic acid

In 1992, the CDC recommended that pregnant women get .4 mg of folic acid daily to prevent NTDs, and in 1998, the US government mandated adding folic acid to grains and cereals to help them do so. (The folate form in foods is poorly absorbed.) But getting this much folic acid from even fortified foods isn’t that easy, so in 2003, clinical management guidelines  from the American College of Obstetricians and Gynecologists called for folic acid in pill form for pregnant women.

Through the 1990s, recommendations stressed folic acid during the perinatal period – a month before conception and 2 to 3 months after. But somehow, perhaps following a more-is-better philosophy, the time to take folic acid supplements during pregnancy stretched. Some women even continue to take the leftovers after giving birth, perhaps reassured by studies countering concerns that the vitamin might cause heart problems, twinning, allergies, and mask B12 deficiency.

Advised WebMD: “The CDC recommends that you start taking folic acid every day for at least a month before you become pregnant, and every day while you are pregnant. However, the CDC also recommends that all women of childbearing age take folic acid every day. So you’d be fine to start taking it even earlier.”

But is it “fine” to continue taking a high dose of folic acid beyond the point at which the neural tube closes?

Might exposure during the second and third trimesters, when brain development accelerates, lead to more subtle symptoms than the open neural tube that early exposure prevents? Like behavioral ones? It makes sense, because folic acid begins the pathway that adds methyl groups to certain genes, silencing their expression – a great example of an epigenetic effect.

Autism enters the picture rather circuitously.

A widely-reported 2013 study presented evidence that folic acid taken from 4 weeks before to 8 weeks after giving birth lowers incidence of autism. Less widely-reported was a study from two years earlier, from Dr. Junaid and his colleagues, who used white blood cells and animal models to look at what happens later in gestation, mimicking the situation of women who continue to take higher doses of the vitamin throughout pregnancy.

Methylation silences genes.

Methylation silences genes.

Indeed, the experiments showed that exposure to high doses of folic acid past the first trimester causes overexpression of a whole bunch of genes. The list includes XIST, the site that controls methylation (silencing) of one entire X chromosome. This might explain why boys with autism outnumber girls. Males are more vulnerable to the effects of both mutation and epigenetic changes because they only have one X chromosome, and are in this genetic sense the weaker sex. Also underexpressed in the presence of folic acid is the FMR1 gene, which lies behind fragile X syndrome, a common cause of autism.

I’d scribbled notes at Dr. Junaid’s talk in April and read the group’s papers, waiting to blog about the work until the results he discussed were published. That happened, also coincidentally, on the day that I found my baby book nestled among my tattered writing clips.

Dr. Junaid’s group reported in PLoS One last week that prolonged prenatal exposure to folic acid in mice is associated with anxiety, hyperactivity, and increased vocalization, but with no effects on learning memory, or social behavior. Male mice were more likely to respond to the excess than female mice. And they identified nine key genes with altered expression. Not exactly autism, but distinct brain changes nonetheless.

The team is conservative in their conclusion that there may be a “loss of benefit” to prolonged folic acid supplementation, writing: “Unregulated high FA supplementation during pregnancy and throughout the life course may have lasting effects, with alterations in brain development resulting in changes in behavior.”

The increase in number of autism cases parallels folic acid use during pregnancy. Coincidence?

Clearly much more work needs to be done on the link, if any, between extended folic acid supplementation and autism. But IMHO this is the very best type of scientific investigation.

It isn’t a “cure” or a “breakthrough” or even “proof,” which are to me the “F” words of reporting on science. The link isn’t coming from celebrities who speak as if they’ve anointed themselves with PhDs in immunology. The work of Dr. Junaid and his colleagues presents a compelling idea, providing enough information to seed a new hypothesis: Can overexposure to folic acid in the second and third trimesters of pregnancy increase risk of developing autism?

That’s what science is: framing new questions.

PikiWiki_Israel_10876_Alyn_Day_CampSo stay tuned. We aren’t nearly done “rounding up the suspects” in causing autism, but meanwhile vaccine phobia is opening the door to the diseases I had as a child, and some much worse.

Do we really want to return to those long-ago summers when parents feared their kids would spike fevers and become paralyzed in a matter of days?

(Thanks to Wikimedia for images and to my mother for my baby book — and getting me vaccinated.)

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The Menopause Toolkit and Summer Sci-Fi

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eggsOne of the worst feelings a woman of a certain age can experience is when someone stupidly asks, “When is your baby due?” and points to the bulge that is not in fact a baby bump, but padding that appears once one’s ovaries have run out of eggs.

And so when researchers from Monash University in Australia published this week, in the journal Climacteric, a “practitioner’s toolkit” to help primary care providers recognize and possibly treat symptoms of menopause, I was intrigued, and then thrilled to discover the phrase “central abdominal fat deposition (even in slim women).” Guilt over the intractable status of my middle began to fade.

I wrote about the menopause toolkit for Medscape, quoting one ob/gyn who loved it, another who thought it stated the obvious. News aggregators parroted the press release, a few dropping in a “breakthrough” or two, as if a woman in the throes of menopause doesn’t know it.

Heraldic_hourglass.svgFiona Jane, MD and Susan Davis, MD and their colleagues created the toolkit, which is more a labyrinth of linked flowcharts than something you’d use to change a tire or clean teeth. The investigators tapped their clinical experience, published diagnostic algorithms, various position statements, and the peer-reviewed literature. The information-packed toolkit is also available in stand-alone form. It targets women over 40, and is so detailed that the International Menopause Society has endorsed it for global use.

I learned a few things.

In addition to discovering that my bulge is due to putting up with low estrogen instead of replacing it (I’m a DES daughter of a mom who had breast cancer, so no thanks, plus some estrogen products come from horse pee), I became aware from the toolkit that “formication” means “crawling sensations on skin.” A biologist might not mind that one so much.

I learned that “dyspareunia” is painful intercourse, which I would have known about had I paid more attention to those Osphena ads on TV. (My husband is in love with the willowy Osphena lady).

I also learned from the menopause toolkit that in addition to hormones served up in all sorts of contraptions and dosages, women take antidepressants, clonidine, gabapentin, eye of newt, and undergo hypnosis and cognitive behavior therapy and something called stellate ganglion blockade to temper what the docs call “vasomotor symptoms” or “hot flushes,” but the rest of us call “hot flashes.”

Having read the flowcharts several times for Medscape, I’d like to make a few recommendations for extending the menopause toolkit.

ISHERB_Caveman1. Some entries require more information than fits in the tiny boxes of the flowchart. Specifically, “no interest in sex” as a symptom may simply reflect the fact that a woman’s partner is an australopithecine. Or she’s exhausted. Or she refuses to take hormones to reinstate someone else’s idea of what should be her sex drive. “Poor sleep?” Please.

2. A few entries could use more graphic descriptions. “Dyspareunia” might be more recognizable as “agony when a giant pole is repeatedly shoved up a desiccated orifice.”

Firetora3. “Hot flush” sounds like a function of a bidet. How about “awakening stark naked drenched in a pool of sweat?”

4. The toolkit mentions “overall diminished well-being” and depression, anxiety, and irritability. Might these so-called symptoms instead be reactions to such external stressors as an adult child returning home? Costly medical care? Pressure at work? Being ignored or taken for granted?

5. Despite the above, I suggest adding “sudden cessation of higher brain functions, particularly recall, reasoning and concentration” as a description of the well-known “menopause brain.”

Water_drops_by_Ximeg_24.12.12-046. The toolkit seems to ignore the sudden loss of bladder control that is a hallmark of menopause, unless it is subsumed under the rather vague “localized urogenital symptoms.” The sounds of a dripping faucet, waves crashing ashore, or rain can all precipitate an event, as can unanticipated laughter. (See Poise pads)

7. Add the vivid dreams, such as iridescent eels writhing out of all body openings.

8. I’ll let my husband Larry have the final word: Another indication of menopause is a partner joining the witness protection program.

PiolinmarcianocolorP.S.: MY TAKE ON SUMMER SCI-FI ON TV: The Leftovers and Under the Dome are explorations of religion with science a mere backdrop, but Extant hit it out of the park.

The Leftovers is the HBO adaptation of Tom Perrotta’s novel that explores the aftermath of a Rapture-like phenomenon that suddenly whisks away 2 percent or so of global humanity. Under the Dome is the second season of the TV version of the Stephen King book, and this week’s episode concluded with a dramatic if anti-science “We are all here for a reason.” After watching the two shows back-to-back I can only conclude that the missing 2 percent from one show somehow ended up under the dome of the other.

In the premier of Extant, on CBS, Halle Berry’s astronaut character Molly Woods returns from a 13-month solo mission preggers. In flashbacks aboard the ship she looks just as great in her form-fitting suit as Sigourney Weaver did in Alien before that reptilian thing blasted out of her non-menopausal middle.

Molly comes home to second husband John (Goran Visnjic aka Dr. Luka Kovac from ER, so glad to see him again!) and his invention, their young son Ethan who is a “humanic,” some sort of android/Damien devil child. After just one episode, Extant seems to have recombined Rosemary’s Baby, V, The Omen, Village of the Damned, Alien, the Exorcist, the X-Files, and even Blazing Saddles.

Ico_specieStay tuned. I know I will.

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Wilson Disease – A Genetic Success Story

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800px-Penny_cents_copper_Lincoln_coin_macroA woman I never met, Ingrid, has taught thousands of students about Wilson disease, an inborn error of copper metabolism. But she never knew it, and I wish I could tell her.

COPPER CONTROL GONE AWRY
Wilson disease is an inborn error of copper metabolism in which the body can’t mop up excess free copper. The element accumulates in the liver, gets into the bloodstream, and enters the brain. Untreated, it’s invariably fatal.

Also known as “hepatolenticular degeneration,” Wilson disease affects 1 in 30,000 (see the National Organization for Rare Disorders) and is autosomal recessive, inherited from carrier parents and affecting both sexes.

The Wilson Disease International Association has a facebook page, but it isn’t as packed and chatty as those for the other genetic diseases I visit often. And Wilson disease has hardly been in the news for astonishing recent progress in the way that cystic fibrosis and  Duchenne muscular dystrophy have. (Recent posts on DNA science have covered these two diseases.

That’s because Wilson disease is treatable. But it wasn’t when Ingrid became ill and then developed a bizarre set of symptoms.

Wilson disease is an inborn error of copper metabolism. It builds up.

Wilson disease is an inborn error of copper metabolism. It builds up.

A YOUNG WOMAN ON A PSYCH WARD
I read about Ingrid in 1992, in a magazine article. I did some research and included her story in the first edition of my textbook,  Human Genetics: Concepts and Applications, in a boxed reading on how genetic diseases affect metabolism of nutrients, minerals in her case.

At the risk of plagiarizing myself, the section began:

Ingrid is in her early thirties. She lives in a geriatric ward of a state mental hospital, unable to talk or walk. Although her silly-looking grin and drooling make her seem mentally deficient, Ingrid is alert and communicates by pointing to letters on a board. It is hard to believe that in 1980 she was a vivacious, normal high school senior.

Ingrid suffered increasingly odd symptoms: after the initial abdominal pain and headaches, she developed slurred and gravelly low-pitched speech, loss of balance, and altered handwriting. Following a multi-year diagnostic journey, telltale greenish-brownish rings around Ingrid’s irises finally prompted a psychiatrist to recognize Wilson disease. These Kayser-Fleischer rings are thought to be deposits of copper.

Copper deposits ring the irises in people with Wilson disease. (Wikimedia)

Copper deposits ring the irises in people with Wilson disease. (Wikimedia)

It was only then that helpful treatment began. A drug called penicillamine enabled her to excrete the excess copper in urine the color of bright new pennies,” I wrote.

Penicillamine is a chelating agent, a compound that encloses a metal and escorts it out of the body. (“Chelate” is actually Greek for “crab’s claw.”) Ingrid took the first in a series of drugs to treat Wilson disease. Today patients typically take triethylene tetramine and zinc acetate for four to six months, and then lifelong maintenance on the second drug. (A new clinical trial will evaluate Wilson disease drugs to treat a form of melanoma caused by mutation in the gene BRAF. )

I was amazed at the entry for Wilson disease in Online Mendelian Inheritance in Man (OMIM; the bible for geneticists), from 1956:

Almost overnight, Wilson disease became one of the few inherited metabolic disorders for which there was effective therapy.

We don’t often hear about treatable genetic disease, and if we do, the strategy is often not this straightforward.

The midbrain in Wilson disease resembles a giant panda on MRI.

The midbrain in Wilson disease resembles a giant panda on MRI.

120px-Basal_ganglia_1A brain scan at some point might have revealed that Ingrid had the “giant panda sign“ – the appearance of midbrain structures in later stages of Wilson disease. Early-onset osteoporosis, arthritis, heart disease, and kidney problems also arise, and for 5 percent of people with Wilson disease, severe liver damage makes a transplant vital. Psychiatric symptoms include depression, anxiety, mood swings, psychosis, suicidal thoughts. The person may be confused and clumsy.

booksINGRID LIVES ON IN MY TEXTBOOK

New editions of my genetics textbook bloomed into life every two years since that first edition from 20 years ago. Stories about real people came and went as I rewrote every other year, but Ingrid’s tale remained.

So imagine my surprise when last week I received this email, from Phyllis Crane.

Hello Dr. Lewis,
My 16-year-old granddaughter is taking a summer class at the University of California, Riverside. The textbook used is your book Human Genetics (2012). I was browsing through the book and on page 21 read the story about Ingrid, who was diagnosed with Wilson disease.

I have been a speech pathologist since 1972 and a clinical psychologist since 1987. In the early 1980′s, I worked at Metropolitan State Hospital in Norwalk, California in the skilled nursing ward. My responsibility was as a Speech Pathologist. Ingrid was one of my patients. When I read about her in your textbook, I was stunned and of course recalled our time together.

When I worked with Ingrid, it was before computers and we developed augmentative communication tools for our patients who were unable to speak. Ingrid’s inability to speak was due to dysarthria weak muscles). Those communication tools consisted of a picture board and an alphabet board. With computers those tools developed into software with the computer producing synthesized speech.

At the same time that I worked with Ingrid, I was referred another individual with Wilson disease with whom I worked on an outpatient basis. He and Ingrid became aware of each other and started to communicate. When my contract with the state hospital came to an end, the ward was closed and the patients moved to another state hospital in Camarillo, California.

I visited Ingrid one time with my other patient, but then lost contact with her. Eventually Camarillo State hospital also closed and is now the site of one of our state universities. I’m thinking that it was at the time of that closure that Ingrid went to live with a family member.” (This is how the entry in my textbook ends, circa 2011.)

I’m assuming that she is a whiz on the computer now,” Phyllis wrote another time, asking that I give her contact info to Ingrid. My answer, that alas I didn’t know what had become of Ingrid, sent Phyllis on a search.

It didn’t take me long to find her obituary. Sad for me, but Ingrid will live on in your book. She would have been thrilled to know she has had an impact on others,” Phyllis wrote.

Ingrid Innecken, born May 21, 1962, had died on August 1, 2010, peacefully.

LESSONS LEARNED FROM INGRID
Zebra_face

1. It is important to evaluate all symptoms and think of the zebras, not just the horses. A depressed and anxious teen may not be like all the others. That tendency to lump may be why 16-year-old David Acott, in the UK, needed an emergency liver transplant just this past May. Diagnosis of Wilson disease had taken 2 years, with doctors not seeing beyond his depression and anxiety, until his eyes yellowed and urine darkened and someone finally diagnosed Wilson disease.

2. Exome and genome sequencing dominate headlines, but good old-fashioned clinical diagnosis will always be important. Ingrid’s diagnosis came from a clinician looking closely at her eyes, and seeing something highly unusual, the unmistakable rings of copper. Diagnosis for Wilson disease is testing for free copper (most of the mineral is bound to a protein called ceruloplasmin) in the blood, urine, and liver. A genetic test confirms mutations in the gene encoding copper-transporting ATPase 2 (ATP7B). And low-tech alphabet boards did for Ingrid what computers do today.

3. Presentations of genetic diseases can be extremely tricky because of their variability. More than 500 mutations have been identified for Wilson disease, including the gamut of point mutations, deletions, duplications, and copy number variants. Mixing and matching of mutations in compound heterozygotes – people with two different mutations – makes for an astounding diversity in age of onset (2-70), different responses to drugs, and lifetimes of changing subsets of symptoms.

4. Today I would have hesitated to describe a person with a disease who might be recognized in my textbook without her permission. We live in a peculiar world of sometimes paralyzing anonymity due to HIPAA, yet details down to the odor of cystic fibrosis farts broadcast, with names, on social media.

(Dept. of Energy)

(Dept. of Energy)

But I’m glad I noticed Ingrid’s story and included it all these years. She will be in the eleventh edition of my human genetics textbook, due out this fall. Thank you Ingrid for teaching the world about Wilson disease.

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