There's solace in numbers in the world of rare diseases

In the world of rare diseases, the story of the Daniels family in Kraaifontein, Cape Town, is probably typical.

For instance, it took parents Gail and Colin Daniels more than 11 years to put a name to the condition—cystinosis—that had dogged their daughter, Danielle, since birth. It is a disease that has stunted her growth, slowed her learning, made her a fixture in doctors’ offices and hospital wards and subjected her to a rigid diet of supplements and boosters.

The family had its first scare when Danielle was hospitalised when she was only a few months old. By age two, doctors looked at her small frame and bowed legs.
She “waddled”, her mother said. She suspected that her child had rickets, a disease, common in Africa, that is characterised by the softening of what are meant to be growing bones. It is caused by a shortage of both vitamin D and calcium.

Narrowing down the condition
But after months of tests, mad dashes to the hospital, a string of specialists and a babble of misdiagnoses, doctors finally narrowed down her condition to Fanconi syndrome.

Named after a Swiss paediatrician, the syndrome affects the ducts or tubes leading from the kidney. These ducts are meant to salvage essential nutrients from fluids passing through the kidneys. But in this syndrome the ducts are unable to do so and precious glucose, carbohydrates, phosphates, amino acids and minerals are passed out in the urine. Without those essential nutrients a rogue’s gallery of troubles follow, rickets and weak bone formation—leading to that waddling and underdevelopment—among them.

There is no cure for Fanconi syndrome. Instead, patients are put on a lifelong course of boosters, supplements, vitamins, phosphate replacements and citrates to make up for the shortfall of minerals.

So for the years that followed Danielle’s life revolved around daily handfuls of pills, potions and powders. She dared not skip a dosage. “It’s normal now,” she says of this regimen.

But, despite the medication, her problems persisted. There were threats of kidney failure, she was in and out of hospital and her eyesight weakened enough to scare the family. Also patients are commonly lethargic, so learning is slow.

Her mother, a teacher, became increasingly frustrated with evasive doctors. So she started her own research, foraging whatever she could from newspapers and the web. “The funny thing was that I couldn’t tell the doctors anything I knew,” she says. “They didn’t want me to know.”

But it was this research that pointed her in the direction of cystinosis. “The name kept coming up whenever you read about Fanconi.”

Naming the disease
Cystinosis borrows its name from a namesake gene, the cystinosis gene. Also known as CTNS, the gene provides the instructions to produce a transport protein—cystinosin—inside compartments in the cell known as lysosomes.

Inside these lysosomes, the cystinosin is broken down into its smaller building blocks, amino acids, including one known as cystine. Living up to its job title, the cystinosin then carries the cystine out of the lysosomes.

When it is unable to do so, the cells produce too little cystinosin or the cystinosin is too weak to carry out its transport duties. Cystine accumulates in the lysosomes and grows into crystals. These crystals then destroy the lysosomes, the cells and ultimately the body’s tissues.

The crystals typically form in the brain, liver, thyroid, pancreas, muscles and particularly in the kidneys and eyes. In the kidneys it damages ducts that can lead to full-blown kidney failure, necessitating kidney transplants. In the eyes the cystine crystals build up in the cornea, triggering extreme sensitivity to light (photophobia) and eventual blindness.

Cystinosis can be put down to a stroke of poor genetic luck. Both parents, unaffected by the condition, have to carry the faulty CTNS gene. Each parent then passes on a copy of that gene to their child.

Statistically, there’s a 25% chance that parents carrying the mutated gene will have a child with cystinosis. Gail and Colin have a second child, a son, Dane (20), who does not have cystinosis.

A childhood disease, cystinosis is considered rare. It is said to affect one child in every 100 000 to 200 000 live births. According to available statistics, only about 2 000 people around the world have been diagnosed with cystinosis. But elementary mathematics—one in 200 000 in a world population of 6,7-billion people—would suggest that that number is way off the mark.

“A lot of children probably die from this condition without it being diagnosed, especially in the developing world,” said Dr Peter Nourse, the paediatric nephrologist at Cape Town’s Red Cross Children’s Hospital who treats Danielle.

With about 14 patients at Cape Town’s Red Cross and Tygerberg hospitals, Nourse has good reason to think that the disease is more common than statistics bear out. “We haven’t worked out the true incidence in South Africa, but it does seem that there are quite a lot of cases, actually,” he says.

Treatment
Although there is no cure for cystinosis, there is a treatment in a drug called cysteamine. It was Gail who stumbled on it in a newspaper article about another Red Cross doctor who was treating cases of photophobia with eye drops he’d cooked up, using cysteamine as the main ingredient.

Cysteamine breaks down the stored-up cystine into a similarly named amino acid, cysteine, and a cysteine-cysteamine mix, both of which are flushed out of the lysosomes. But one needs regular fixes: a cysteamine drink (drug plus distilled water) has to be downed every six hours like clockwork, the eye drops administered hourly.

Also, the cocktail tastes “disgusting”, so doctors, parents and caregivers have their work cut out feeding it to children four times a day, says Nourse. Even hardened nurses have been known to recoil at the smell.

Danielle is more fortunate. She takes an easier-to-keep-down capsule version of cysteamine, Cystagon, which costs about R18 000 a month, a bill footed by the family’s medical aid scheme.

Cystagon was developed as an orphan drug—medication for rare diseases—in the United States, where it has been prescribed for cystinosis for the past 15 years. It’s not readily available or licensed in South Africa, though. So the family also had to jump through a number of bureaucratic hoops to have the drug imported.

There’s the potential of an even sweeter pill on the horizon. Raptor Pharmaceuticals in the US is making headway on a delayed-release version of the treatment, to be known as DR Cysteamine. It’s hoped that DR Cysteamine will cut out some of Cystagon’s side effects and halve the daily dosage.

“The new formulation should be better tolerated and taken only every 12 hours,” reports Margret Kamel, a research coordinator with a team conducting phase-three human trials on the drug at Emory Children’s Centre in the US.

Joining forces
But how is it that cystinosis is worthy of all this attention? After all, the markets for treatments for most rare diseases are usually too small to coax companies to do the necessary R&D.

“Funding for rare diseases is very uneven,” points out cystinosis guru Dr William A Gahl, clinical director at the National Human Genome Research Institute in Maryland in the US. “Cystinosis, too, languished for a while.”

But the condition piqued academic interest because of its “intriguing basis” as a lysosomal transport defect, says Gahl. Researchers hope that treatments for a few dozen inherited metabolic disorders, also linked to faulty lysosomes, can be developed on the back of cystinosis studies.

Cystinosis also benefits from the American Orphan Drug Act, which allows pharmaceutical companies to sell their orphan drugs without fear of competition for a full seven years.

Families push for research
But most of the credit should go to one American family. Under the banner of the Cystinosis Research Foundation (CRF) they established in 2003, Nancy and Geoffrey Stack, whose 19-year-old daughter Natalie has cystinosis, have raised around $12-million, money they distribute in research grants. That makes the family the largest supporter of cystinosis research in the world.

It was a CRF-funded researcher,
for example, who did the groundwork for the new delayed-release cysteamine. The foundation’s latest project is the establishment of the first and only international patient registry, named the Cure Cystinosis International Registry.

“Our goal is to get every patient with cystinosis to register,” says Nancy. “By doing so, we’ll have a more thorough picture of cystinosis and its complications, providing our research teams with information they so desperately need to discover novel treatments and a cure.”

And a cure is exactly where the CRF is headed next. Recently the foundation established the CRF Gene Therapy Consortium, which includes experts in gene and stem-cell therapy.

Working with mouse models, researchers at Scripps Institute in San Diego have used stem cells extracted from bone marrow to express a more shipshape CTNS gene. This revitalised gene was then able to reverse the accumulation of cystine in the cell and subsequent cell death.

The scientists are optimistic but cautious. “These data are very promising, but the translation from mice to humans does not always reproduce the same effect,” says Dr Stephanie Cherqui, assistant professor in the department of molecular and experimental medicine at Scripps.

Support and education
The Daniels family is playing its part. In 2010 Gail and Colin established the South African Cystinosis Support Group, affiliated to the US-based Cystinosis Foundation, which is distinct from the Stacks’ Cystinosis Research Foundation, but the groups work hand in hand on, for example, the international registry.

Gail is mother hen to others in the South African group, largely state patients with no medical aid. She’s produced easy-to-follow information pamphlets for the group and meets and advises members. Until recently Colin covered most of the running costs and lent other assistance, such as cooler bags to preserve the cysteamine drink. (The group now receives a small donation from a Dutch couple, Jan and Marjolein Bos, who run a similar group in the Netherlands.)

Gail wants group members to have the same kind of support she received through the Cystinosis Foundation. “The foundation was the best thing that could have happened to us,” she says, “because we could speak to people who understood what we were saying and what we had gone through.”

Her mentor on the foundation is the eightysomething founder, Jean Hobbs-Hotz. “There is a treatment for cystinosis,” says Hobbs-Hotz. “We want the medical community to understand the disease so they can make a proper diagnosis and for families to understand the disease and the need for compliance.”

Danielle remains on the verge of kidney failure, but her family is keeping their eye on the future. “To say the worst is over won’t be very realistic,” says Gail. “But we are hopeful and prayerful that by God’s grace a cure for cystinosis will be found so that Danielle and many other sufferers will be able to enjoy good health.”

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