UCSD Cystine Determination Laboratory

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Cystinosis: Symptoms and Treatment

SYMPTOMS

Symptoms include polyuria and polydipsia, urinary losses (including electrolytes, glucose, phosphate, and amino acids), retarded growth and poor appetite.

Cystinosis patients are treated with a combination of therapies. The tubular dysfunction is managed by oral electrolyte supplements in the form of sodium and potasium salts. Because of their tubular dysfunction, affected individuals excrete excessive amounts of urine and must consume large amounts of water throughout the day and night. The tubular dysfunction causes urinary losses of phosphate which can lead to rickets. Rickets is treated with a combination of sodium or potassium phosphate and vitamin D.

TREATMENTS

Aminothiol therapy depletes the lysosomes of cystine and is used to prolong glomerular function and improve growth.
CystagonTM (cysteamine bitartrate) was the first aminothiol approved by the United States Food and Drug Administration (August 1994).
ProcysbiTM is a delayed release formulation of cysteamine bitartate which was approved by the FDA in 2013.
CystaranTM is a formulation of cysteamine.HCl used to reduce or prevent crystal formation in the cornea of the eye, approved in 2012.

In addition to their renal disease, cystinosis patients often become hypothyroid and are treated with thyroxine.
Almost all cystinosis individuals experience retarded growth and fall below the third percentile for height. The growth improvement with aminothiol therapy usually allows the patient to maintain growth along a percentile, but does not usually aid in achieving "catch up" growth. Many children with cystinosis receive growth hormone and some have had improvements in height to well above the third percentile.
There is evidence indomethacin increases appetite, decreases urine volume, decreases water consumption and improves growth in pretransplanted patients with cystinosis. (See references for additional info.)

CYSTEAMINE THERAPY IN POST TRANSPLANT CYSTINOSIS
Nephropathic cystinosis was long considered primarily a renal disease, but it's now recognized as systemic disorder which eventually effects many organ systems. A certain portion of post-transplant patients develop retinal blindness and corneal ulceration, muscle weakness and wasting, difficulty swallowing, diabetes due to destruction of the pancreas, infertility (in males) and, rarely, central nervous system deterioration. These problems generally occur in the second, third, or fourth decade in patients who never received cysteamine therapy. All of the patients over age 30 seen at the NIH have experienced a major, lifestyle-altering complication of the disease, and the evidence suggests that the complications are progressive in nature.

The only possible countermeasure against this progression is to attack the cystine accumulation with cysteamine (CystagonTM or ProcysbiTM). This drug reduces the cystine content of cultured cells by over 90%. When given orally to cystinosis patients, the white blood cell cystine concentration can be lowered to 5-10% of the untreated level, and this suggests that other cells, tissues, and organs are depleted of their cystine as well. In fact, there is substantial evidence that long-term oral cysteamine therapy depletes cystinosis patients' muscle of cystine, and the liver and kidney appear to benefit as well.

Functionally, chronic oral cysteamine therapy has been shown, in three different studies, to retard deterioration of kidney function and to enhance the growth of cystinosis patients. In the most recent study, cysteamine therapy was demonstrated to increase renal function in the first three years of life. Long-term oral cysteamine therapy was also shown to prevent the need for thyroid hormone replacement in many cystinosis patients. Finally, topical cysteamine eyedrops dissolve corneal crystals and relive photophobia.

With all this evidence that cysteamine may help preserve non-renal tissues, we at the NICHD began treating post-transplant patients. We have now treated 21 individuals for more than 5 years with cysteamine. Only 5 of these patients had significant complications of cystinosis, and four of the five had their complications before starting cysteamine. In contrast, 13 of 28 patients treated for less than 5 years experienced a significant complication with cystinosis. In view of the harmful effects of chronic cystine accumulation, and the indications of the effectiveness of cysteamine therapy in various tissues and organ systems, oral cysteamine should be considered for use by post-transplant cystinosis patients. It is already treatment of choice for pre-transplant patients throughout the world.

- William A. Gahl, M.D., Ph.D.


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