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The evolving treatment paradigm for cystinosis

Cystinosis is a rare, degenerative, inherited disease in which the amino acid cystine accumulates abnormally in all cells of the body. The reason for the accumulation is due to a defective mechanism to transport cystine out of the cells. Cystine crystals accumulate in the kidneys, eyes, liver, muscles, pancreas, brain and white blood cells, which causes a variety of symptoms. Complications can include muscle wasting, swallowing difficulties, breathing difficulties, diabetes, hypothyroidism, late puberty, dementia and blindness. The incidence of cystinosis is between one in 100,000-200,000 live births.

There are three clinical forms of cystinosis. The most common and severe form is infantile nephropathic cystinosis. It is responsible for approximately 95 per cent of cases. Symptoms begin in infancy, often before one year of age and include failure to thrive, height retardation, rickets, vomiting, loss of appetite, constipation, and photophobia. The earliest abnormalities are seen in the kidney and are known as Fanconi syndrome, the symptoms of which include excessive thirst and excessive urination. Minerals and nutrients are lost in the urine and result in several problems such as rickets, which occurs when low levels of phosphate and vitamin D are present.

Another form of the disease, late-onset nephropathic cystinosis, is not usually diagnosed before the age of 12 years and the disease progresses slowly. Cystine crystals are present in the cornea and conjunctiva of the eye and in the bone marrow. Kidney function is impaired and individuals with this form of cystinosis may also develop Fanconi syndrome.

Finally, adult (benign or non-nephropathic) cystinosis begins in adulthood and does not result in any kidney impairment. Cystine crystals accumulate in the cornea and conjunctiva of the eye and photophobia is present.

Diagnosis

One of the world’s leading experts on the disease, Dr William Gahl, recently delivered a presentation in Beaumont Hospital, Dublin, on developments in the treatment of cystinosis. Dr Gahl is the current Clinical Director of the National Human Genome Research Institute, at the National Institutes of Health main campus in Bethesda, Maryland, US. Following his presentation, he spoke to the Medical Independent (MI) about the diagnosis and treatment of the disease, focusing especially on the most common form, infantile nephropathic cystinosis.

“The kids will get poor growth from six-to-nine months of age and they will fall off their growth curves,” Dr Gahl said.

“That will be a hint. Then another hint will be that they will urinate a lot and get dehydrated. Some of them will have to go to hospital because they are so dehydrated and acidic. That is a sign of Fanconi syndrome — part of the kidney that is supposed to reabsorb all these small molecules and water, and fails to do so. Once you have Fanconi syndrome, the doctors will pick up that it could be cystinosis.”

According to Dr Gahl, cystinosis is sometimes misdiagnosed as Bartter syndrome, which is another kidney disease that involves electrolytes being secreted out of the urine improperly.

“That is a classic misdiagnosis. Occasionally, patients are misdiagnosed with diabetes — regular diabetes and also diabetes insipidus, which is marked by a failure to reabsorb water. Eventually people should come to the diagnosis, but the very first diagnosis may be somewhat different.”

Measuring elevated white blood cell cystine content is the cornerstone for the diagnosis. The diagnosis can be confirmed by molecular analysis of the cystinosin gene. Corneal cystine crystals are invariably present in all patients with cystinosis after the age of one year.

The earlier cystinosis is diagnosed, the better, due to the damage the disease inflicts on the kidney.

Treatment

While there is no cure for the disease, Dr Gahl’s laboratory was instrumental in demonstrating the safety and efficacy of cysteamine (β-mercaptoethylamine) therapy, a treatment that depletes cells of cystine. Cysteamine therapy, along with kidney transplantation, has greatly improved the outcomes for cystinosis patients.

Cysteamine blunts the decline in renal function and improves the linear growth of the patients with cystinosis, although it does not ameliorate the defect in renal tubule transport. Oral therapy should be initiated as soon as the diagnosis is made.

The first studies on the drug were conducted in 1978 but it was not approved by the FDA in the US until 1994, even though it was widely used in practice from the mid-1980s.

Dr Gahl pointed to the development of a delayed-release capsule, cysteamine bitartrate, which was approved in the US in 2013, as a notable recent treatment development. It allows twice-daily dosing, whereas the immediate-release capsule has to be administered every six hours, including throughout the night, to prevent nocturnal accumulation of cystine.

Due to impaired kidney function, children and adolescents also need to take mineral supplements such as calcium, potassium, vitamin D, phosphate and sodium bicarbonate to replace those lost.

The development of medication has revolutionised the treatment of the condition, which in the 1950s caused death in infancy and childhood. The advent of kidney transplants for patients in the 1960s and 1970s prolonged life span, but could not prevent complications and early death.

“Cysteamine has made a huge difference for patients with regard to life expectancy,” according to Dr Gahl.

“It brought the mortality rate from 50 per cent down to 8 per cent. And those were mortalities due to complications due to complications of cystinosis, largely non-renal complications, the muscle problems, some of the brain problems, things like that. So it completely changed that around. The other major effect is that it delayed the need for kidney transplant by at least 10 years on average.”

Side-effects of the medication include nausea/vomiting and a ‘rotten egg odour’ on the breath and skin.

Kidney damage

Unfortunately, kidney transplants are still an inevitability for patients with cystinosis due to the damage it causes to the organ within the first year of life.

“By the time a child with classic cystinosis is diagnosed, there has been significant damage to the kidney already done,” he said.

“The average age of diagnosis is 14 months. By 14 months, the glomeruli have been damaged considerably. Maybe you have lost 30 per cent of them; maybe you have lost 50 per cent of them.”

A 2010 study in Molecular Genetics and Metabolism on the area found the presence of substantial numbers of atubular glomeruli (ATG) in end-stage cystinotic renal tissue.

Compared to normal renal tissue, cystinotic kidneys at end-stage had 69 per cent ATG and 30 per cent atrophic glomeruli. Normal renal tissue had 4 per cent ATG and zero per cent atrophic glomeruli (pb0.0001 for both comparisons).

These non-functioning nephrons may be the end result of cell loss from the tubules and represent the final stage of the ‘swan-neck deformity’ of the proximal renal tube. The process is consistent with the previously-reported increased apoptosis in renal tubule cells due to lysosomal cystine storage.

This kidney damage caused by cystinosis requires careful management, according to Dr Gahl.

“The physician has to, after diagnosis and in terms of treatment, replace the kidney losses. By kidney losses, I mean the small molecules that have been secreted out in the urine have to be replaced, so things like phosphate and potassium and bicarbonates and water, and sometimes calcium. All these things need to replaced properly and that requires large doses. And there are other things — if the thyroid goes, some patients need thyroid medication and some of them may also need testosterone replacement later on. Also, their eyes need to be taken care of too.”

The corneal crystals of cystinosis are not dissolved by oral cysteamine, since the cornea is avascular. Cysteamine eye drops, however, dissolve the crystals if given up to 10 times per day. Photophobia is also relieved within three weeks, even with less frequent dosing.

Due to the availability of cysteamine and other treatments, Dr Gahl believes that the outlook for patients with the condition is much improved.

“If I had to make a guess, I see no reason why someone treated from birth can’t live a normal life span,” he said.

“I think the reasons that mitigate against that are that the person has to go through a kidney transplant, maybe two kidney transplants, and receive immunosuppressive medications. Those things could have a bearing on life span.”

Gene therapy

Next-generation sequencing to diagnose the disease earlier and gene therapy are also potential developments that could revolutionise the treatment of cystinosis, he noted.

 All three types of cystinosis are caused by mutations in the CTNS gene. Mutations in the gene lead to a deficiency of a transporter protein called cystinosin. Within cells, this protein normally moves cystine out of the lysosomes, which are compartments in the cell that digest and recycle materials.

The condition is inherited in an autosomal recessive pattern, meaning both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

“People are working on gene therapy, but they have been working on it for about five years or so,” according to Dr Gahl.

“It will be a while, which is how I look at gene therapy. The best thing that can be done for this disease is newborn screening, because if you diagnose it early, then all the issues are about longevity and not needing a kidney transplant and not developing the late complications.”

In summary, Dr Gahl said that oral and topical cysteamine help preserve function of all affected organs in cystinosis and that the medication should be given to patients of all ages early. He concluded that early and diligent therapy is essential and that newborn screening for cystinosis would expand cysteamine’s benefits.

For more information on cystinosis and support organisation Cystinosis Ireland, see www.cystinosis.ie.

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