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Black Pee Disease Offers New View of Arthritic Joints

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.

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. 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

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.

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.

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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