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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Wilson Disease – A Genetic Success Story by DNA Science Blog, unless otherwise expressly stated, is licensed under a Creative Commons Attribution 3.0 Unported License.

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